Joint Annual Research Report 2004 - The Royal Marsden

royalmarsden.nhs.uk

Joint Annual Research Report 2004 - The Royal Marsden

ANNUAL RESEARCH REPORT 2004

The Royal Marsden

NHS Foundation Trust


The Royal Marsden

NHS Foundation Trust and

The Institute of Cancer

Research together form

the largest Comprehensive

Cancer Centre in Europe

Our Mission is

to relieve human suffering by

pursuing excellence in the fight

against cancer.

This will be achieved through:

Research and development;

• Education and training of medical,

healthcare and scientific staff;

• Provision of patient care and treatment

of the highest quality;

• Attraction and development of resources

to their optimum effect.


CONTENTS

Review of 2004 – from the Chairmen and Chief Executives 4

Facts and Figures 12

Academic Dean’s Report 13

Technology Transfer Report 17

Research Themes

Review Articles

CANCER BIOLOGY Dying to survive: how can tumour cells escape death 20

Dr Pascal Meier

CANCER THERAPEUTICS/ The PKB protein: an important target for cancer treatment 24

CANCER BIOLOGY

Dr Michelle D Garrett

CANCER THERAPEUTICS Designer drugs for the cancer genome 28

– Drug Development Professors Stan Kaye and Paul Workman

CANCER THERAPEUTICS Myeloma research: novel therapeutic approaches 34

– Haemato-Oncology Professor Gareth Morgan

CANCER THERAPEUTICS New therapies for colorectal cancer 38

– Colorectal Cancer Professor David Cunningham

CANCER THERAPEUTICS Melanoma: our understanding of the disease increases but 42

– Skin Cancer prevention is still the best medicine

Mr J Meirion Thomas

IMAGING RESEARCH & Rapid advances in the diagnosis and treatment of cancers 46

CANCER DIAGNOSIS

Drs Gary Cook and Val Lewington

– Nuclear Medicine

RADIOTHERAPY/CANCER Prostate cancer: new approaches are allowing a better 50

BIOLOGY – Prostate Cancer understanding of the disease and its treatment

Professor David Dearnaley and Dr Amanda Swain

HEALTH RESEARCH Genetic epidemiology: a tool for finding the causes of cancer 54

– Epidemiological Studies Professor Anthony Swerdlow

HEALTH RESEARCH Lymphoedema, diet and body weight in breast cancer patients 58

– Dietary Interventions Dr Clare Shaw

Research Reports on the Internet 62

Our Research Centres, Departments, Sections and Units 64

Senior Staff and Committees 66

3


Review

of 2004

From the Chairmen

and Chief Executives

REVIEW OF 2004

Tessa Green

Chairman

Lord Faringdon

Chairman

Cally Palmer

Chief Executive

Peter Rigby

Chief Executive

The Royal Marsden

NHS Foundation Trust

The Institute of

Cancer Research

The Royal Marsden

NHS Foundation Trust

The Institute of

Cancer Research

We are delighted to present our Annual Research

Report for 2004, which records another year of

important achievements and significant progress

in cancer research. It contains in-depth reviews of

recent, exciting developments in several areas of our

work, and provides addresses for various web resources

which give comprehensive information on all aspects

of our activities.

The Institute of Cancer Research and The Royal

Marsden NHS Foundation Trust form the largest

Comprehensive Cancer Centre in Europe, and one of the

largest in the world, which has an outstanding national

and international reputation. Our mission, “to relieve

human suffering by pursuing excellence in the fight

against cancer”, is carried out within a framework of

activities in research and development, education and

training, and the treatment and care of people affected

by cancer. We work, like other world-class centres of

excellence, in a truly international context and in

partnership with many research institutions and

funding agencies.

The availability of the sequence of the human

genome, and of the many other genomes which help us

to understand the meaning of the blueprint that makes

each of us, has enormous implications for cancer

research. It means that we can now systematically

identify all of the genes involved in the progression from

a normal cell to a tumour cell. The challenge for the

future is to exploit this genetic information for the

benefit of cancer patients and our joint scientific

strategy seeks to put in place the skills and resources


Cancer genes

Scientific Strategy:

from cancer genes

to patient treatment

and prevention.

Molecular

pathology

Genetic

epidemiology

Therapeutics

Prognostic

Diagnostics

Biomarkers

Aetiology

Response

to therapy

Targets

Drugs

Imaging

Targeted

therapy and

Prevention

necessary to do this. This is entirely appropriate since it

was our researchers, Professors Peter Brookes and

Philip Lawley, who, some forty years ago, first showed

that chemicals that cause cancer act by damaging DNA,

the stuff of which our genes are made. This heritage

continues with the Cancer Genome Project, led by

Professor Mike Stratton, and undertaken in partnership

with the Wellcome Trust’s Sanger Institute. It will provide

us, for the first time, with a complete description of the

genetic alterations which cause the disease, and the

initial results are hugely exciting.

Our joint research strategy seeks to exploit this

information in three areas: genetic epidemiology,

molecular pathology and therapeutic development.

In genetic epidemiology, information from the Cancer

Genome Project and other genetic analyses will be used

in very large, population-based studies to try to discover

the environmental and lifestyle factors that contribute to

the development of cancer. Some we know, smoking

being the most obvious, but for many cancers our

present understanding of causation is rudimentary.

Our work in molecular pathology will use the genetic

knowledge to devise not only new and more sensitive

ways of detecting the disease earlier but also much

more precise ways of staging its progression, with

consequent benefit to patient management. Knowing all

the mutations in a particular tumour will help to identify

the molecular targets for therapeutic intervention. Our

strategy in therapeutic development will target these

precisely defined molecular abnormalities, and it is

greatly enhanced by substantial increases in hospital

facilities for imaging, radiotherapy and early drug trials.

5


The new Genetic

Epidemiology Building,

which will open in the

autumn of 2005.

Research Highlights

The most important event so far in our Genetic

Epidemiology Programme occurred in September with

the launch of the Breakthrough Generations Study. This

exciting new partnership with Breakthrough Breast

Cancer seeks to understand the environmental, lifestyle

and genetic factors that cause breast cancer. Led by

Professor Tony Swerdlow, Chairman of the Section of

Epidemiology, and Professor Alan Ashworth, Director of

the Breakthrough Toby Robins Breast Cancer Research

Centre, the study will recruit over 100,000 women and

follow them for forty years. It will collect data on their

genetics, their reproductive history, their hormonal

status and their lifestyle, and from such information

we hope to deduce the factors that cause the disease.

Such knowledge is essential if there are ever to be

effective prevention programmes. This study, and others

of a similar nature, will be greatly facilitated by the new

Genetic Epidemiology Building, which will open in the

autumn of 2005, and has been made possible by a

£9.2M grant from the Higher Education Funding

Council for England’s Science Research Investment

Fund. As well as providing state of the art

accommodation for the scientists involved, the building

will provide us with the capacity to store the vast

number of samples, and paper questionnaire records,

that will be collected from the participants.

Our understanding of the genetic basis of cancer

advances rapidly. Professor Mike Stratton, with

colleagues in the Cancer Genome Project, showed that

a subset of lung cancer patients carry mutations in the

ErbB2 gene. This encodes a tyrosine kinase and is thus

a highly promising target for therapeutic intervention,

given that we know that mutations in the related

ErbB1 gene confer sensitivity to the drug Iressa.

Professor Nazneen Rahman, team leader in the Section

of Cancer Genetics and Honorary Consultant in Medical

Genetics, studied a very rare condition called Multiple

Variegated Aneupoloidy. Aneuploidy, a feature of many

tumour cells, means that they have the wrong number

of chromosomes, and it has long been argued whether

it is a cause or a consequence of cancer. Children with

the condition have an elevated risk of cancer. She

showed that it results from mutations in the Bub1B

gene, which we knew from studies in yeast is involved

in the process by which the daughter chromosomes are

separated at each cell division. Her data show clearly

that aneuploidy is a cause, it significantly increases the

risk of cancer. Dr Arthur Zelent, a member of the new

joint Section of Haemato-oncology, was part of an

international collaboration that showed that a

transcriptional repressor called Pokemon is a critical

factor in tumour formation. In the absence of this

protein, cells are completely refractory to oncogeneinduced

transformation while its over-expression causes


REVIEW OF 2004

tumours. It is highly expressed in human cancers in a

fashion related to clinical outcome and is thus an

attractive target for therapeutic intervention.

In Molecular Pathology one of our main objectives

is to find ways of telling whether prostate cancer,

diagnosed following a PSA test, is aggressive and

requires immediate clinical intervention, or whether

it is indolent, ie it will grow slowly and the patient can

be spared treatment, needing only careful monitoring.

It was thus of great significance when Colin Cooper, the

Grand Charity of the Freemasons Professor of Molecular

Biology, and his colleagues showed that the E2F-3 gene

is over-expressed in prostate cancer, and that the levels

of expression correlate very well with the

aggressiveness of the tumour. It will now be important

to see if this observation can be developed into a

routine test. Moreover, because we know that the

E2F-3 protein functions in the control of the cell cycle,

we may also have identified a therapeutic target. To

complement this, the hospital has a major clinical

research programme in early prostate cancer called

Active Surveillance, in which suitable patients are

monitored closely rather than treated immediately,

and it seems that the majority of these patients will

completely avoid the need for radical treatments.

This was a year of much progress in the

development and validation of new treatment

modalities. For a considerable number of years

Professor Paul Workman, Director of the Cancer

Research UK Centre for Cancer Therapeutics, and his

colleagues have been studying inhibitors of the

molecular chaperone HSP90, which is involved in the

proper folding of a number of proteins known to play

key roles in oncogenesis. Together with the team of

Professor Laurence Pearl, Co-Chairman of the Section

of Structural Biology, they have developed novel small

molecule inhibitors of the chaperone, in a highly

Expression of E2F-3

protein (brown)

detected by

immunohistochemistry

in primary prostate

cancer

7


Professor Stan Kaye

who heads the new

Drug Development Unit.

Research volunteers in the

hyperbaric oxygen chamber

at the Institute of Naval

Medicine at Haslar

productive collaboration with Vernalis Ltd, and it was

a significant step forward when the major

pharmaceutical company Novartis licensed this

technology in order to take it forward into the clinic.

The initial stages of the clinical development of a

new anti-cancer drug depend upon Phase I trials, in

which the safety and pharmacokinetic properties of

the molecule are assessed, although with the new

generation of molecularly targeted therapies, efficacy

data may also be gathered at this stage. In order to

significantly increase our capacity for Phase I trials

the Royal Marsden, with the most generous support

of the Oak Foundation, has constructed a new Drug

Development Unit which will be headed by Professor

Stan Kaye, the Cancer Research UK Professor of

Medical Oncology. New treatments can be developed

much more rapidly if their pharmacology, localisation

and molecular targeting can be verified and early

responses assessed sensitively, and new functional

imaging techniques offer the opportunity to do this

efficiently and non-invasively. The Royal Marsden has

installed a new PET-CT facility, and an additional MRI

machine has been purchased.

Once there is evidence that a new drug induces

clinically significant responses, before it can be

marketed and widely prescribed its value must be

rigorously evaluated in large Phase III trials. Ms Judith

Bliss, the Chairman of the Section of Clinical Trials,

co-ordinated a major international trial which showed

that the aromatase inhibitor exemestane is of

significant benefit to post-menopausal women who

have had breast cancer. Last year we reported that

Professor Ian Smith, Head of the Breast Unit, had

led the initial trial of another aromatase inhibitor,

letrozole, now shown to be of great benefit. This new

class of drug, which acts by blocking the synthesis of

the female hormone oestrogen, will markedly change

the clinical management of breast cancer. Professor

David Cunningham, Head of the Gastro-Intestinal

Cancer Unit, was a leader in trials which showed that

Capecitabine, an oral pro-drug of 5-Fluorouracil, and

the monoclonal antibody Cetuximab, are agents that

can be highly effective in colorectal cancer patients.

Large, randomised trials of surgical procedures

are not common but Mr Meirion Thomas, Consultant

Sarcoma Surgeon at the Royal Marsden, led a trial,

again co-ordinated by Ms Judith Bliss, which showed

clearly that the excision width, ie the amount of tissue

surrounding the tumour that is removed with it, is a

highly influential factor in the survival of patients with

malignant melanoma. Perhaps even more unusual was

a trial led by Professor John Yarnold which explored

the use of hyperbaric, ie high pressure, oxygen in the

treatment of lymphoedema. Swelling of the arms

is a common side-effect in women who have had

surgery and radiotherapy for breast cancer and it can

have a real effect on their quality of life. Sitting in a

hyperbaric chamber, of the sort used to help deepsea

divers recover from the bends, appears to bring

great benefit and further, larger trials are now

being planned.


REVIEW OF 2004

While there have been great successes in the

treatment of cancers in children, most notably with

leukaemia, the therapies can lead to major problems

in later life, and there are tumours, like

neuroblastoma, for which there are no effective drugs.

The development of new treatments for paediatric

cancers is thus a high priority, and it is something that

must be pursued in an academic environment as the

number of patients is not sufficient to attract the

attention of pharmaceutical companies. We were thus

delighted when Andy Pearson accepted the Cancer

Research UK Chair of Paediatric Oncology. He was

formerly Professor of Paediatric Oncology and Dean

of Postgraduate Studies in the Faculty of Medical

Sciences at the University of Newcastle, and is

Chairman of the United Kingdom Children’s Cancer

Study Group. His mission is to exploit our expertise

in cancer genetics and drug development in order to

identify and validate new, targeted therapies for

childhood cancers, and to lead the paediatric

oncology service in the hospital.

New Developments

As noted above, in the context of the Breakthrough

Generations Study, The Institute is currently constructing

a new building on the Sutton Campus that will provide

state of the art accommodation for the Sections of

Clinical Trials and Epidemiology, and also for essential

support functions like Information Technology, the

Registry and Facilities. We have been informed of our

provisional allocation from the next phase of the

Science Research Investment Fund, and are likely to

expend these monies, some £11M, on major

renovations of the Old Building at the Chester Beatty

Laboratories in Chelsea and of the Haddow Laboratories

in Sutton, and on the purchase of new equipment.

Better Healthcare

Closer to Home

The Royal Marsden and The Institute have been

contributing to consultation on a new model of care

in South West London called ‘Better Healthcare Closer

to Home’. This will involve the creation of a critical

care hospital, co-located with The Royal Marsden and

The Institute in Sutton, and ten local care hospitals.

The overall aim is to create a service and academic

centre of excellence on the Sutton site, in collaboration

with NHS partners and St George’s Hospital Medical

School, supported by the delivery of more locally based

day care and outpatient facilities for patients. It will

also enable us to make significant investment in our

infrastructure, improving the environment for patients

and staff and for our combined research enterprise.

News of our staff and

their achievements

We were delighted that Professors Colin Cooper

and Stan Kaye were elected to the Fellowship of the

Academy of Medical Sciences. One fifth of our faculty

have now been accorded this honour, an excellent

achievement. Professor Laurence Pearl was elected to

membership of the European Molecular Biology

Organisation, in recognition of his outstanding

contributions to structural biology. A vital part of our

activity is the attraction of the brightest and best young

clinicians and scientists. We were thus particularly

pleased that Drs Tim Crook, who will shortly join the

Breakthrough Centre, and Chris Parker, team leader in

the Section of Radiotherapy and Honorary Consultant

in Clinical Oncology, were awarded prestigious Cancer

Research UK Clinician Scientist Fellowships. We were

delighted that Dr Clare Shaw was appointed as the

first Consultant Dietician in the NHS (see her article

on page 58).

The Old Building at

the Chester Beatty

Laboratories in

Chelsea due for

major renovations

9


Financial Facts and Figures

The principal sources of income and the expenditure

of our joint institution are summarised in the Facts

and Figures page (page 12). Full and detailed

statements of the financial accounts of The Institute

of Cancer Research (August 2003 to July 2004) and

The Royal Marsden NHS Foundation Trust (April 2004

to March 2005, to be published in September 2005)

are separately recorded in our respective Annual

Reports and Accounts. In the financial year ending on

31 March 2005, the Trust met its key financial objectives

and achieved a balanced budget. In the financial year

ending on 31 July 2004, The Institute achieved a

balanced budget on unrestricted funds after transfers.

Its expenditure on research grew by 10.7% from the

previous year, with increases in research expenditure

across a number of research Sections.

Overall, the combined

annual turnover of

our organisation was

£203.1 million, with

89% of this total being

devoted to research

activities and patient

care services.

Government funding for our joint research activities

contributes 42% of the total resources for research.

Our success rate in competing for research funding

from external sources continues to be outstanding,

at 75% of the value of all applications for peerreviewed

grants to medical charities and government

funding agencies. The Institute is particularly indebted

to its major funding partners – Cancer Research UK,

Breakthrough Breast Cancer, Leukaemia Research,

the Wellcome Trust, the Medical Research Council,

Department of Health, and many other medical

research sponsors.

New commercial partners collaborating in drug

development at The Institute and supporting clinical

trials at the Royal Marsden include: AstraZeneca,

Novartis, Vernalis Ltd, Astex Technology Ltd, Pfizer,

Antisoma and BTG.

Many organisations also contribute support by

providing funds for studentships at The Institute and

clinical fellowships at the hospital. The Royal Marsden

and The Institute are grateful to all the numerous

organisations and supporters who have made

investments in our research activities.

Fundraising

The Royal Marsden publicly launched its £30 million

appeal to finance a number of major projects to provide

a range of new facilities and leading edge equipment

which will enhance the hospital’s research capacity as

well as provide improved treatments for patients.

Generous gifts from an anonymous charitable

foundation, the Oak Foundation, the Garfield Weston

Foundation, John and Catherine Armitage, the PF

Charitable Trust, the Wolfson Foundation, the Arbib

Foundation, Martin Myers and a number of other trusts

and private individuals, brought the sum pledged to £24

million by the end of the year. The loyal support of the

hospital’s staff and patients, their families and friends

and the general public contributed some £2 million to

that total. Our thanks go to all the dedicated people

who have done so much to bring the appeal’s final

target in sight so speedily.

The Institute continues to receive significant support

from charitable trusts, companies and an increasing

number of individuals. Our Everyman Male Cancer


REVIEW OF 2004

Campaign attracted unprecedented support during 2004

which included partnerships with Topman, The Football

Association, The Professional Footballers’ Association and

Gillette UK, among many others. We extend our most

grateful thanks to all those who have contributed to

our continuing success, including The Grand Charity of

Freemasons, the Garfield Weston Foundation, ICAP plc

and the many individuals, trusts and companies who

have supported The Institute through donations or

attendance at fundraising occasions. With over 90%

of our total income going directly into research

The Institute remains one of the most cost-effective

cancer research organisations in the world.

It is a great pleasure to present this, our joint

Annual Research Report for 2004. We pay tribute to

everyone who has contributed to our achievements this

year, not least our outstanding scientists and clinicians

whose excellence and dedication keep The Royal

Marsden NHS Foundation Trust and The Institute of

Cancer Research at the forefront of world-class

cancer research.

Tessa Green

Chairman

Cally Palmer

Chief Executive

The Royal Marsden

NHS Foundation Trust

Lord Faringdon

Chairman

Professor Peter Rigby

Chief Executive

The Institute of

Cancer Research

11


FACTS AND FIGURES

Facts and Figures

Human Resourses

Total staff numbers 2,945

(includes 12 part-time students)

Financial Summary

Total income: £203.1 million.

(The Royal Marsden’s figures are provisional and unaudited for the year end 31/03/2005)

E

A

Income £m

£m Expenditure

Cancer Research UK 18.0

D

C

B

Breakthrough Breast Cancer 4.3

Leukaemia Research 0.8

Other Charities 4.0

Medical Research Council 1.9

Other Govt (UK, EU, US) 5.5

Industry & Commerce 3.6

83.2 Research & Development

and Academic Activities

A 27.5 % Scientific Staff (808)

B 16.2 % Medical care (475)

C 23.7 % Nursing care (700)

D 4.0 % Students (120)

E 28.6 % Central support (842)

Private Patients 25.8

Legacies & Donations 12.2

Investments & Property 6.7

Other Income (inc Capital) 16.1

Higher Education

Funding Council 13.1

NHS Executive (R&D) 23.9

97.9 Patient Care & Treatment

NHS (Patient Care) 67.3

1.3 Fundraising & Public Relations

6.4 Administritive Support

13.2 Captial Development &

Development Fund

1.1 Other Expenditure


Academic Dean’s

Report 2004

Our academic achievements in 2004 have been

outstanding, and we congratulate our newly appointed

professors and qualifying students. Our series of seminars

and lectures cover a broader scope than ever before,

allowing our students to develop an integrated

understanding of the varied disciplines in cancer research.

ACADEMIC DEAN’S REPORT 2004

Bob Ott

PhD FInstP CPhys

Bob Ott is Professor of

Radiation Physics and

the Academic Dean of The

Institute of Cancer Research

The Faculty, Teachers

and Awards

The achievements of our senior scientists and clinicians

continue to be recognised by the conferment of

academic titles of the University of London. In 2004,

the title of Professor of Clinical Oncology was conferred

upon Dr Michael Brada, Professor of Haematology on

Dr Gareth Morgan and Professor of Childhood Cancer

Biology on Dr Kathy Pritchard-Jones. The title of Reader

in Cell Signalling was conferred upon Dr Richard Marais.

Conferences, Lectures

and Seminars

A highlight of The Institute's academic year is the

Annual Conference. This aims to share knowledge and

expertise across The Institute and the Royal Marsden,

and to encourage collaboration in research through

common purpose. Staff and students contribute in a

variety of ways. The blend of lectures, student

presentations and team poster presentations displays

the breadth of research.

The major themes of the conference, held at the

University of Surrey, were ‘Hot topics in biology’,

chaired by Dr Kathy Weston, ‘Ovarian cancer’, chaired

by Professor Stan Kaye, ‘New targets’, chaired by

Professor Paul Workman, ‘Haematological oncology’,

chaired by Professor Gareth Morgan and ‘Biologically

targeted radionuclide therapy’, chaired by myself.

Student oral presentations were of the usual high

quality with first prize being awarded jointly to Mary

Haddock and Katrina Sutton. Student poster prizes

were won by George Tzircotis (first prize) and

Paraskevi Briassouli (second prize).

The Institute continues to attract outstanding

scientists of international renown for its Distinguished

Lecture series. Notably this year, presentations were

given by Professor John Burn, Institute of Human

Genetics, International Centre for Life, Newcastle, UK;

Professor Hedvig Hricak, Department of Radiology,

Memorial Sloan-Kettering Cancer Center, New York,

USA; Professor John Bell, John Radcliffe Hospital,

Oxford, UK; Dr Terry Rabbitts, MRC Laboratory of

Molecular Biology, Cambridge, UK; and Professor

Michel P Coleman, Epidemiology and Vital Statistics,

London School of Hygiene & Tropical Medicine, UK.

The annual Link Lecturer was Dr Charles L Sawyers,

13


Table 1. University of London – degrees awarded

Doctor of Philosophy

Mark Atthey

Joana Raquel de Castro Barros

Mounia Beloueche-Babari

Bilada Bilican

Anthony James Chalmers

Geoffrey David Charles-Edwards

Antigoni Divoli

Ellen Mary Donovan

Sandra Easdale

Mathew James Garnett

Christopher Mark Incles

Nicola Ingram

Osman Jafer

Nathalie Just

Antonios Kalemis

Meinir Krishnasamy

James Michael George Larkin

Young Kyung Lee

Brian Leyland-Jones

Alessandra Malaroda

Alison Maloney

Laura Mancini

Joo Tim Ong

Andrew Paul Prescott

Nancy Jean Preston

Sonia Caroline Sorli

Antonello Spinelli

Lindsay Anne Stimson

Laura Louise White

Steven Robert Whittaker

Simon Wilkinson

Daniel Williamson

Master of Philosophy

Matthew Green

Paul Rogers

Doctor of Medicine

Irene Miles Boeddinghaus

Judith Ann Christian

Nilima Parry-Jones

John Nicholas Staffurth

Katherine Anne Sumpter

Sucheta Vaidya

Joint Department of Physics

Cell and Molecular Biology

Clinical Magnetic Resonance Group

Marie Curie Research Institute

The Gray Cancer Institute

Clinical Magnetic Resonance Group

Joint Department of Physics

Joint Department of Physics

Cancer Therapeutics

Cell and Molecular Biology

School of Pharmacy

Cell and Molecular Biology

Molecular Carcinogenesis

Clinical Magnetic Resonance Group

Joint Department of Physics

Pain and Palliative Medicine

Cell and Molecular Biology

Joint Department of Physics

Cancer Therapeutics

Joint Department of Physics

Cancer Therapeutics

Clinical Magnetic Resonance Group

Joint Department of Physics

Clinical Magnetic Resonance Group

Pain and Palliative Medicine

Cell and Molecular Biology

Joint Department of Physics

Cancer Therapeutics

Joint Department of Physics

Cancer Therapeutics

Cell and Molecular Biology

Molecular Carcinogenesis

Medicine

Cancer Therapeutics

Professor of Medicine at the UCLA Jonsson Cancer

Center, USA. The Link Lecture embodies the continuum of

laboratory and clinical research which characterises the

joint research endeavour of The Institute and the Royal

Marsden, and the appointment carries with it a Visiting

Professorship. Dr Sawyers’ lecture on ‘Kinase inhibitors in

cancer therapy’ was a fitting and well-received exemplar

of the translational approach to cancer research.

Professor David Dearnaley delivered his inaugural

lecture in September, entitled ‘Cinderella comes to the

ball: a personal perspective on prostate cancer research’

chaired by Professor Alan Horwich. Finally the Inter-site

Lecture series, designed to foster greater links between

the Chelsea and Sutton sites, went from strength to

strength with a further nine seminars. These complement

the large number of seminars with external

speakers that are organised by individual Sections.

Students

Demand for entry to our PhD research-training

programme remains very high, with many high-calibre

students from the UK and overseas being keen to join

us. A total of 641 enquiries generated 581 formal

applications. The number of new MPhil/PhD students

admitted this year was 24, making a total of 99 fulltime

PhD students in The Institute. We also received

one part-time MPhil/PhD registration, and 11 students

registered for the degrees of MD and MS.

Lord Faringdon presenting

prizes for the best PhD

students to Geoffrey

Charles-Edwards and

Mathew Garnett.


ACADEMIC DEAN’S REPORT 2004

We acknowledge and thank those organisations

which have supported our students during the past year:

Cancer Research UK, Breakthrough Breast Cancer, the

Medical Research Council, The Royal Marsden NHS

Foundation Trust, Leukaemia Research, the Engineering

and Physical Sciences Research Council and AstraZeneca.

The Institute's Graduation Ceremony for students

who completed their awards in 2004 took place at the

Brookes Lawley Building in Sutton. For students and

their families it provided a perfect setting for the

celebration of their awards. Two MPhils, six MDs and

32 PhDs were awarded by the University of London

(Table 1). The Institute's Chairman, Lord Faringdon,

presented prizes for the best PhD students to Geoffrey

Charles-Edwards and Mathew Garnett. Dr Trevor Hince,

Professor Allan van Oosterom, Dr Peter Bailey, Dr Mark

Bodmer and Dr Tony Diment were appointed as

Members of The Institute in honour of their

contributions towards advancing The Institute's

objectives. Mr Neil Ashley, Lord Bell, Mr Rory and

Mrs Elizabeth Brooks, Mr Raymond Mould, Lady Otton,

Mrs Susan Rathbone, Mr Julian Seymour and Mr David

Wootton were appointed as members of The Institute’s

Development Board whose objective is to assist with

The Institute’s fundraising. Miss Sue Clinton, Dr Maggie

Flower, Mr John Harris, Mr Alan Hewer, Mrs Betty Lloyd,

Mr Kenneth Markham, Mrs Ruth Marriott, Mr Geoff

Parnell and Mr Bill Warren were honoured as Associates

of The Institute in recognition of their many years of

service and achievements.

Visitors

The Institute had the usual large number of visitors

to its laboratories. We are fortunate in having the

resources of the Haddow Fund with which to foster

important links with the international scientific

community attracted by the excellence of the science

at The Institute. This year the Haddow Fund supported

the International Testicular Cancer Linkage Consortium,

the 3 rd International Conference on the Ultrasonic

Measurement and Imaging of Tissue Elasticity hosted

by The Institute, and visits from Dr Helga Ögmundsdóttir

to work with Dr Sue Eccles and Dr Asher Salmon to

work with Dr Ros Eeles.

Interactive Education Unit

Kathryn Allen PhD, Director

The Interactive Education Unit (IEU) was established at

The Institute in 1999 with the remit to develop Weband

CD ROM-based educational resources

(www.ieu.icr.ac.uk). The overarching aim of the

IEU is to promote and disseminate the educational,

research and clinical activities of The Institute in order

to improve the treatment, care and quality of life of

people with cancer. The Unit’s work was highlighted

as an area of good practice in the educational audit of

The Institute in early 2004, undertaken by the Quality

Assurance Agency. The IEU website was a Platinum

award winner in the 2004 MarCom creative awards,

a leading international marketing and

communications competition.

IEU projects are developed in collaboration with

leading scientists and clinicians at both The Institute

and the Royal Marsden. The Unit has three key markets:

scientists and students, healthcare professionals and

patients and the public.

Scientists and students –

developing resources to aid research/

career development

Examples of projects in this category are:

The Study Skills Website – this website was launched

in July 2002 on The Institute’s intranet. It aims to

provide students with a range of transferable skills

such as time management, presentation,

organisation and writing. The website is part of

Figure 1.

A page from the

bioinformatics module

of Perspectives in

Oncology – the cancer

science website.

15


ACADEMIC DEAN’S REPORT 2004

Figure 2.

The Relax and Breathe

resource, CD version.

The Institute’s strategy to meet the skills training

requirements for students funded by the Research

Councils. Latest additions to the site include sections

on writing a paper and writing a thesis.

Perspectives in Oncology, the cancer science website

– this website (see Figure 1) was launched in June

2004 to provide students at The Institute with a

thorough and connected grounding in the field of

cancer science. The site emphasises how discoveries

in scientific research translate into clinical care and

highlights how the fields of physics, biology,

chemistry and medicine all contribute to

understanding, managing and treating cancer.

The site was launched initially with five modules,

covering causes and prevention of cancer, common

cancers, therapies, genetics of cancer and

bioinformatics. Five further modules are scheduled

for development in 2005–06. Perspectives

in Oncology was a Gold Finalist in the 2004

MarCom creative awards competition.

Healthcare professionals –

supporting evidence-based practice

Examples of projects in this category are:

A Breath of Fresh Air CD ROM – this interactive

guide to managing breathlessness in patients with

advanced lung cancer is based on research work

pioneered at The Institute and the Royal Marsden.

Over 14,000 copies of A Breath of Fresh Air have

been distributed worldwide since its launch in 2001.

The programme is provided free to healthcare

professionals thanks to generous sponsorship from

the Diana, Princess of Wales Memorial Fund Project,

Macmillan Cancer Relief and Marks & Spencer, and

can be ordered by calling 0800 9177263. The

programme is currently being updated.

RT Plan, the conformal radiotherapy website – this

website, currently in development, will help to

educate oncology clinicians and trainees in 3D

conformal radiotherapy planning in patients with

localised prostate cancer.

Pain Management CD ROM – currently in

development, this interactive guide to managing

pain in cancer will provide a comprehensive

overview of the subject, featuring case histories and

management tools to use with patients.

Patients and the public – cancer education

An example of a project in this category is:

Relax and Breathe – this resource, developed in

collaboration with Macmillan Cancer Relief, is

available in both CD and audiotape format. It

features practical guidance and exercises on

relaxation. The resource is designed to help people

with lung cancer cope with their breathlessness, but

can also be used by healthcare professionals

wanting to learn and practise relaxation. Over 7,000

copies of the CD, 2,000 of the audiotape and 1,500

of the healthcare professionals resource pack have

been distributed so far. Relax and Breathe is

available free thanks to sponsorship from Macmillan

Cancer Relief, and can be ordered by calling the

Macmillan Resources line on 01344 350 310,

specifying the preferred format. Relax and Breathe

was a Gold Finalist in the 2004 MarCom creative

awards competition (see Figure 2).


Technology Transfer

Report 2004

The Institute and the Royal Marsden work with commercial

partners so that research findings can be developed and

distributed for the benefit of patients worldwide.

The Director of Enterprise outlines the highlights of this

technology transfer activity during 2004.

TECHNOLOGY TRANSFER

Susan Bright

PhD

Dr Susan Bright is

Director of Enterprise

of The Institute of

Cancer Research

The Enterprise Unit at the The Institute, working

together with the Royal Marsden, has again had a

very active and successful year.

The objective of the Enterprise Unit is to facilitate

the transfer of research outputs to commercial

organisations that can provide development resources.

Inventions are thereby disseminated to as wide a

patient base as possible.

Our technology transfer

effort focuses primarily on

ensuring that the route of

development chosen is

capable of delivering

maximum patient benefit.

Return of revenue to The Institute and the Royal

Marsden is a welcome additional result of the work

of the Enterprise Unit. The Enterprise Unit continues to

work in partnership with Cancer Research Technology

Ltd (CRT) who take the lead in the commercial

exploitation of Cancer Research UK funded work.

The Unit also works closely with British Technology

Group (BTG), The Wellcome Trust and other technology

transfer organisations as appropriate to specific projects.

Astex Technology Ltd

(PKB Collaboration)

In 2003 The Institute began a collaboration with

the fragment-based, drug discovery company Astex

Technology Ltd on the development of novel

inhibitors of the enzyme protein kinase B (PKB).

It is anticipated that these inhibitors will be useful

anticancer drugs. Professors David Barford, Paul

Workman and Dr Michelle Garrett are project leaders

at The Institute for this collaboration. Good progress

continues to be made and the partnership is clearly

illustrating the synergy that can be achieved when two

strong research teams work together. Two series of

novel potent PKB inhibitors have been identified.

17


PETRRA Ltd

The Institute continues its active involvement in the

spin-out company PETRRA, which was founded to

develop the novel positron emission tomography (PET)

camera invented by The Institute, the Royal Marsden

and the Rutherford Appleton Laboratory, based on the

research of Professor Bob Ott. The first clinical trial of

the camera began at the Royal Marsden in 2002 and

was successfully completed in 2004. The camera

demonstrated its ability to produce high-quality images

efficiently and cheaply. PETRRA has secured additional

funding from a seed investment fund. A new CEO will

be appointed and PETRRA will actively seek a

commercial partner in 2005.

Domainex Ltd

In 2002 The Institute played a key role in establishing

the new spin-out company Domainex together with its

partners, University College and Birkbeck College.

Domainex secured investment from the Bloomsbury

Bioseed Fund and Dr Keith Powell was appointed CEO.

Institute founder scientists are Professor Laurence Pearl

and Dr Chris Prodromou. Domainex was established to

exploit a novel technology developed by the founders

that enables rapid analysis of the structure and function

of complex proteins. The technology can be applied to a

wide range of oncology targets. In 2004 Domainex

signed its first commercial contract with Inpharmatica

and obtained additional funding from the DTI. The

company now has funds to last until 2006 and further

commercial contracts are actively being pursued.

Chroma Therapeutics Ltd

The Institute continues its active involvement in

the spin-out company Chroma, which was founded to

develop novel anticancer drugs based on enzymes

involved in the remodelling of chromatin. Chroma is

based on work at The Institute and the University of

Cambridge. Professor Paul Workman is The Institute's

founder scientist. In 2004 Chroma’s first product

entered Phase I clinical trials and significant progress

was made in a number of key projects. In addition

the company raised an additional £15 million of

venture capital funding ensuring a good foundation

for the future.

PIramed Ltd

The company PIramed Ltd was founded in 2003 based

on research arising from the Ludwig Institute of Cancer

Research, Cancer Research UK and The Institute.

Professor Paul Workman is The Institute’s founder

scientist. PIramed has funding from JP Morgan Partners

and Merlin Biosciences and is developing a number of

drug products principally focused on inhibitors of the

PI3 kinase superfamily. Good progress was made in

2004 on the lead project and a clinical candidate has

been selected.

Vernalis Ltd

(HSP90 collaboration)

In 2002 The Institute began a collaboration with the

Cambridge based biotechnology company RiboTargets

(now Vernalis Ltd) to develop inhibitors of the molecular

chaperone Hsp90. Hsp90 plays an important role in

directing the function of many key intracellular

‘oncogenic’ proteins. Inhibitors of Hsp90 will affect the

function of these proteins and this will result in an

anticancer effect. The Hsp90 project combined the

resources and skills of both Vernalis and The Institute; at

The Institute the lead scientists on this programme were

Professors Laurence Pearl and Paul Workman. The

collaboration ended its first phase in 2004 having

successfully developed several novel, potent Hsp90

inhibitors. Vernalis has now secured a licensing

agreement with Novartis who will take these

compounds into the clinic.


TECHNOLOGY TRANSFER

Figure 1.

The Variable Aperture

Collimator (VApC).

BRAF Collaboration with

The Wellcome Trust

In 2002 The Institute began a collaboration with The

Wellcome Trust and Cancer Research UK to develop

novel drugs to inhibit the enzyme BRAF. The

identification of BRAF as a cancer target came out

of The Institute's involvement with the Wellcome

funded Cancer Genome Project. The joint venture is

managed by Institute scientists, the Enterprise Unit,

CRT and The Wellcome Trust. In addition the company

Astex Technology Ltd joined the collaboration in 2004.

The project manager is Dr Richard Marais from The

Institute and the Wellcome Trust is leading the

commercialisation effort. The collaboration has identified

two distinct chemical series of promising novel BRAF

inhibitors. A partnership with a pharmaceutical company

is the objective for 2005.

Quinazolines

(BTG collaboration)

Professor Ann Jackman has worked for a number of

years on novel quinazoline anti-cancer drugs. Her first

success in this area was the compound Tomudex which

is now on the market and earning royalties. Three other

quinazoline drugs with different mechanisms of action

are in development, all in partnership with BTG. One of

these drugs, the compound BGC 9331, is successfully

going through a Phase II clinical trial.

MRI Technology

Professor Martin Leach’s team has developed a number

of novel tools to help in the use and analysis of

Magnetic Resonance Imaging. Several patents have

been filed and there are also a number of items of

proprietary software. The Enterprise Unit is actively

seeking industrial partners for these technologies.

Patents

In total 15 new patents were filed in 2004 directly by

The Institute or in collaboration with other institutions.

One of the patents filed, in collaboration with the

German Cancer Research Center (DKFZ), was for a

method of intensity-modulating a beam of radiation

from a radiation source. The Variable Aperture

Collimator (Figure 1) can be used instead of a multileaf

collimator and also with intensity-modulated

radiotherapy.

Industrial Collaborations

The Institute continues to collaborate with a number of

other industrial partners including AstraZeneca, Novartis,

Antisoma, Pfizer, KuDOS and GSK.

19


CANCER BIOLOGY

Dying To Survive:

how can tumour cells escape death

Identification of a novel mode of caspase regulation and

a better understanding of the molecular mechanisms of

programmed cell death are providing greater insights into

how tumour cells bypass apoptosis and survive.

Pascal Meier

PhD

Dr Pascal Meier is Team

Leader in Apoptosis in

Cancer in The Breakthrough

Toby Robins Breast Cancer

Research Centre at The

Institute of Cancer

Research

All cells are mortal

In multicellular organisms fatal cancers occur when

mutated cells proliferate and survive inappropriately.

The human body is composed of approximately 10 14

cells, which fall into a multitude of diverse cell types.

Given the vast number of cells in our body it is

surprising how little generally goes wrong. One of the

reasons is the body’s astounding ability to correct errors.

All cells have built-in auto-destruct

mechanisms

It is now clear that each cell carries within it a built-in

auto-destruct mechanism, which limits the survival and

expansion of a cell if it becomes potentially harmful or

malignant. Thus, cancer cells that spontaneously arise

out of these 10 14 cells are normally eliminated because

the cell activates its intrinsic suicide programme. This

self-destruct mechanism – called apoptosis – is a key

defence strategy against the emergence of cancer.

Apoptosis and the pathogenesis of disease

With good reason, apoptosis is currently one of the

hottest areas of modern biology. A closer look at the

basis of the pathogenesis of most human diseases

almost always reveals a defect in some component of

apoptosis, which either contributes to the disease or

accounts for it.

Diseases characterised

by the failure of cells to

undergo apoptotic cell

death include cancer,

autoimmune disease

and viral infection. In

contrast, too much

cell death can lead

to diseases such as

neurodegenerative

disorders, AIDS or

osteoporosis.

Apoptosis and organ development

While apoptosis is clearly involved in the pathogenesis

of a variety of human diseases, it is nevertheless also an

essential building block during the normal development

of a multicellular organism. In general, during an

organism’s development there is an initial over-generation

of excess cells from which a final tissue or organ is

ultimately formed. However, during the later stages of

development, dispensable and supernumerary cells are

subsequently eliminated by apoptosis so that a balance

can be achieved of the relative number of cells of

different types, thereby allowing proper organ function.

Apoptosis and homeostasis

Thus, during early development, apoptosis is needed

to sculpt structures such as fingers and toes. Later on

in life, apoptosis is also instrumental to ensure that

organ size remains constant – a process called tissue

homeostasis. For example, during each menstrual cycle

the epithelium of the normal human breast undergoes

a phase of cell expansion. However, later on, a phase of

cell removal follows which reduces the breast back to its

original size. Similarly, during pregnancy and lactation

high levels of cell proliferation and differentiation occur

in the breast, leading to a massive expansion of the

mammary gland. But, after lactation has finished, the


differentiated lactating lobules are no longer required

and are then removed by apoptosis, returning the organ

to its mature resting state. Thus, during adult life, as

during development, numerous structures are formed

that are later removed by apoptosis.

Repair by self-destruction

Substantial evidence indicates that the very same

genetic mutations that trigger uncontrolled cell

expansion, and hence might give rise to cancer, at

the same time also trigger spontaneous activation of

cell death. The finding that the molecular lesions that

generate uncontrolled cell expansion also coordinately

trigger cell death indicates that under normal

circumstances apoptosis acts as a fail-safe strategy

to hinder the expansion of potentially harmful cells. In

this respect, apoptosis acts as part of a quality-control

and repair mechanism that eliminates unwanted cells.

Consequently, cancer can only ever emerge if apoptosis

has been suppressed.

Most types of cancer

cells show an acquired

resistance toward

apoptosis.

Cancer therapies and

apoptosis – reason for concern

The goal of all current cancer therapies, which include

radiation, chemotherapy, immunotherapy and gene

therapy, is the obliteration of the cancer cell. However,

it is now clear that the effects of radiotherapy and

chemotherapeutic agents result in a response by which

the treated cancer cell kills itself by activating its own

in-built self-destruct programme. Thus, the success of

current therapeutic intervention schemes heavily relies

on the ability of the cancer cell to activate its own

apoptosis programme. This exposes a significant

problem with current therapeutic strategies.

Because cancer cells can only ever emerge if the

apoptosis programme is either blocked or dampened,

the very same mutations that permit tumour formation,

by suppressing apoptosis, will also reduce treatment

sensitivity and will therefore contribute to treatment

failure. Not surprisingly, therefore, such therapeutic

strategies often fail to selectively eradicate neoplastic cells.

Understanding the tools of

the ‘Grim Reaper’

To try to resolve how cancer cells bypass apoptosis,

the Apoptosis Team within The Breakthrough Toby

Robins Breast Cancer Research Centre is studying the

machinery that executes apoptosis and the molecular

mechanisms that control this potentially catastrophic

process. Our work concentrates on the engines of the

apoptotic execution programme. The destructive

components of this cell-death machinery consist of a

group of highly specialised proteases (enzymes that

break down proteins) called caspases.

Caspases form the molecular chainsaws of the

self-destruct programme which, when activated, cut

the cell to pieces. Activation of caspases is a key event

in apoptotic signalling and is required to execute cell

death. Caspases are present in every cell at all times,

but remain dormant. However, upon exposure to

DNA damage, chemotherapeutic compounds or

developmental signals, caspases become rapidly

activated. Once active, caspases cleave and destroy a

multitude of polypeptides inside the cell that are vital

for cellular function, shape and integrity. Cells are

destroyed and removed within minutes of caspase

activation – an event which is, self-evidently, potentially

catastrophic and must be tightly regulated.

The last line of defence – IAPs

Certain members of the evolutionarily conserved

inhibitors of apoptosis (IAP) protein family have been

found to function as guardians of the apoptotic

machinery. IAPs were originally identified in viruses but

are also present in animals as diverse as insects and

humans. Most importantly, IAPs suppress apoptosis

extremely efficiently.

Recent studies show that several human IAPs are

strongly upregulated in many cancers. For example,

deregulated levels of the mammalian IAP XIAP are

21


(a)

(b)

Caspase

inactive

DIAP1

IAP-antagonist

DIAP1

Figure 1.

Regulation of apoptosis by

IAPs and IAP-antagonists.

(a) IAPs suppress

apoptosis by directly

binding to caspases,

thereby obstructing the

caspases access to their

substrates. IAPs block

caspases by binding to

caspases and targeting

them for ubiquitylation.

(b) In cells that are

destined to die, levels

of IAP-antagonists become

elevated. Cell death is

induced when IAPantagonists

bind to IAPs,

whereby caspases are

displaced and liberated

from IAP complexes.

observed in non-small cell lung cancer cells. Moreover,

chromosomal translocations of cIAP1 are frequently

found in mucosal-associated lymphoid tissue (MALT)

lymphomas, while Livin/ML-IAP/KIAP is highly expressed

in melanomas.

Caspase

active

DIAP1

DIAP1

Caspase

active and

unguarded

DIAP1

Ubiquitylation

Degradation

Substrate

intact

DIAP1

Degradation

Substrate

cleaved

Proteasome

Survival

Proteasome

Cell

death

The observation that IAPs suppress apoptosis very

effectively and are present in cancer cells strongly

suggests that IAP-mediated inhibition of apoptosis

contributes to tumour pathogenesis, disease progression

and/or resistance to drug treatment.

Mark Ditzel and Rebecca Wilson have investigated

how IAPs suppress cell death. They made the striking

observation that IAPs inhibit deadly caspases by fusing

another protein, called ubiquitin, onto caspases (Figure

1). The ubiquitin label inactivates the caspases and the

cell survives. The fate of proteins that are modified with

a ubiquitin label can vary substantially, with some

polyubiquitylated proteins being disassembled and

destroyed by the cell’s demolition centre, the

proteasome, while others end up in different subcellular

compartments, and yet others are inactivated.

IAPs belong to a specialised group of proteins, called

E3 ubiquitin protein ligases, which transfer ubiquitin

protein labels onto caspases thereby blocking cell death.

Survival through mutual

annihilation

While IAPs label caspases with ubiquitin, caspases are

not the only proteins that are modified with ubiquitin.

Mark Ditzel and Rebecca Wilson also found that, in the

process, IAPs themselves become coated with ubiquitin.

Attaching ubiquitin to IAPs has dire consequences for

the affected IAP itself, since this modification targets it

for proteasomal demolition. Because IAPs represent the

last line of defence against caspase-mediated damage it

appears to be somewhat counterintuitive that the cell

gets rid of its own guardian. So, why should it be

beneficial to a cell to destroy its own protector

The answer to this is that ubiquitin-mediated

instability of IAPs reflects the natural occupational

hazard of being a ubiquitin-handling E3 protein ligase.

The intrinsic instability of IAPs and their anti-apoptotic

activity is intimately intertwined. Genetic and molecular

studies indicate that IAP destruction is in fact essential

for their ability to block apoptosis. Only IAPs that are

unstable and are destroyed are capable of controlling

caspases. This raises the intriguing possibility that IAPs

suppress apoptosis by actively searching out and

destroying activated caspases. In this respect, IAPs and

caspases would be coordinately destroyed in an

altruistic sacrifice.

This discovery has major implications for the

generation of novel therapeutic small molecule

inhibitors designed to block the E3 ubiquitin protein

ligase activity of IAPs.

In the presence of such inhibitors of IAPs, caspases

would no longer be coated with ubiquitin and hence

would remain active and destroy the cancer cell.

Since only cancer cells, but not normal cells,

constantly drive the activation of caspases, such E3-

inhibition is predicted to selectively kill tumour cells.


CANCER BIOLOGY

SMAC ’em dead

It is now clear that apoptosis is implemented by

caspases. To date 11 caspases have been identified in

humans. While XIAP suppresses only three of these, it is

currently unclear how the remaining set of caspases is

controlled.

How caspases are kept quiet

Tencho Tenev and Anna Zachariou have studied how

caspases are kept in abeyance. They made the discovery

that certain caspases carry an evolutionarily conserved

motif, which is designed to attract and bind to IAPs,

hence the name IAP-binding motif (IBM). Normally, this

IBM is buried deep within a dormant, non-active caspase.

However, when the caspase is activated, this motif is

exposed and acts like a magnet for IAPs. Thus, even when

caspases are activated this will not necessarily end in cell

death, because IAPs can home in on active caspases and

smother their destructive potential. The most exciting

aspect of this discovery is that only a tiny motif, in fact,

one single amino acid residue of the caspase, is crucially

involved in anchoring it to IAPs. Mutation of this one

residue completely abrogates the interaction between

IAPs and caspases. Consequently, activated caspases

become invisible for IAPs and therefore are unrestrained

and free to cause mayhem.

The IAP: caspase complex – a new

pharmaceutical target

The fact that such a tiny motif is important for the

caspase:IAP association makes it an exciting

pharmaceutical target. Indeed, preliminary studies using

small molecule chemotherapeutic inhibitors that mimic

this single amino acid residue have already given rise to

very exciting preliminary results. Numerous cancer cell

lines appear to be exquisitely sensitive to such agents.

Cancer cells that have been treated with such IBM

mimetics appear to keel over and die owing to

spontaneous and unrestrained activation of caspases.

The agents break up the IAP:caspase complex thereby

liberating caspases from IAP-mediated inhibition.

Another regulator of IAPs is a protein called SMAC

which activates caspases by directly inhibiting IAPs.

SMAC mimetics are being developed as anticancer

agents acting through promoting apoptosis.

SMAC mimetics seem

not to harm normal

cells, yet selectively

destroy cancer cells.

This selectivity strongly

indicates that cancer

cells are particularly

addicted to IAPs for

their survival.

Breaching the barricade

This SMAC strategy to kill cancer cells is not a novel

man-made creation but actually is a strategy that nature

has evolved to kill cells during the normal sculpting of

the human body. Normal cells that are destined to die

overcome the IAP-mediated roadblock on caspases. A

specialised group of naturally occurring killer proteins

(IAP-antagonists) trigger cell death by directly blocking

the access of IAPs to caspases. The sole function of

these assassin proteins is to bind and antagonise IAPs

thereby displacing and liberating caspases (see Figure

1). Once displaced and relieved of IAP-mediated

inhibition, caspases effect apoptosis.

In the fruit fly Drosophila melanogaster, the world’s

best-known model organism, the activity of IAPantagonists

– which carry intriguing names such as

Reaper, Grim, Sickle, Hid and Jafrac2, is essential for

apoptosis during development. Cells that lack Reaper,

Grim and Hid completely fail to activate the apoptosis

programme – just like cancer cells.

Prospects for the future

Small molecule inhibitors already exist to block IAPs.

Future studies will undoubtedly determine whether such

SMAC compounds can be turned into efficacious small

molecules that enhance the apoptotic mechanism, either

alone or in combination with conventional

chemotherapeutic agents.

23


CANCER THERAPEUTICS/CANCER BIOLOGY

The PKB Protein:

an important target for cancer treatment

The PKB protein is part of a molecular signalling

pathway in the cancer cell that promotes both cell

proliferation and survival. A key objective is to develop

small molecule inhibitors that will block the action of

PKB in the cancer cell.

Michelle D Garrett

PhD

Dr Michelle D Garrett is a

Team Leader in Cell Cycle

Control in the Cancer

Research UK Centre for

Cancer Therapeutics at

The Institute of Cancer

Research

Figure 1.

The cycle of cell

growth and division

– cell proliferation.

A revolution in cancer drug

discovery and treatment

The treatment of cancer patients is undergoing a

major revolution away from the use of conventional

chemotherapy, which can indiscriminately kill all

growing cells in the body, towards novel anticancer

agents that specifically target the molecular

abnormalities of the cancer cell itself. This has been

made possible by the implementation of strategies that

investigate the changes that occur in the genetic

information (the DNA) of a cancer cell.

An example of this is the Cancer Genome Project,

which aims to identify most of the genetic changes that

occur in the majority of common cancers. The role of the

Cell Cycle Control Team in the Cancer Research UK

Centre for Cancer Therapeutics is to understand how

M – Mitosis,

cell division

G2 – Cell

checks DNA

replication

is correct

G1 –

Cell growth

S – Replication

of genetic

information (DNA)

these genetic changes cause misregulation of the cycle

of cell growth and division, a process known as cell

proliferation (Figure 1), and how we can exploit these

abnormalities of the cancer cell to develop new,

targeted anticancer treatments.

Cell proliferation and cancer

The life of a cell in the human body is a complicated

process, often subject to external messages from

surrounding tissues. These messages can tell the cell to

proliferate, through cell growth and division – an event

that can occur when the body needs to replace cells

that have been lost. Once sufficient cells have been

produced, the signal may be withdrawn or a second

signal may be sent telling the cells to stop proliferation.

The genetic changes in the DNA of our cells that cause

cancer often affect how a cell will respond to these

signals. These changes in our DNA can be translated

into alterations in the properties or amounts of proteins,

which are the building blocks of our cells.

A change in just one

protein in a cell can

upset its normal

behaviour so that it will

grow and divide into

two cells – even when

it is receiving messages

to stop.

PKB – an important target

for cancer treatment

PKB and cyclin D1

The protein PKB (also known as AKT) is part of a

signalling pathway in the cell that promotes both cell

proliferation and survival. This pathway receives signals

from the external environment via a receptor at the cell

surface, which then relays the signal to a protein

complex known as PI3 kinase. PI3 kinase then produces


Extracellular

environment

Signal

Receptor PI3 kinase PIP 3 PKB

Figure 2.

The PI3 kinase/PKB

pathway.

Intracellular

environment

Cyclin D1

Proliferation

Other proteins

Survival

Plasma

membrane

of cell

a chemical, PIP3, that binds to and promotes activation

of PKB. Once active, PKB sends signals throughout the

cell via interactions with other proteins to promote both

proliferation and survival (Figure 2).

A key downstream target of PKB is a protein known

as cyclin D1, which is an important regulator of cell

proliferation and currently is under investigation in our

laboratory. PKB acts on proliferation by regulating the

amount of cyclin D1 in the cell (Figure 2). When PKB

is actively sending signals throughout the cell, the level

of cyclin D1 will increase, leading to uncontrolled cell

proliferation, as in cancer. When PKB is switched off,

the level of cyclin D1 in the cell will decrease and cell

proliferation will cease.

The PI3 kinase/PKB

pathway is a major

controller of cell

proliferation and

survival and it can

become misregulated

in cancer.

Overexpression of receptors that

relay signals in cells

In particular, the receptors that relay signals to the PI3

kinase/PKB pathway (see Figure 2) are overexpressed

in lung and breast cancer, whilst genetic alterations

that cause misregulation of PI3 kinase itself and the

chemical messenger it produces have been discovered

in colon, breast, prostate and ovarian cancer. PKB is

also overexpressed in a number of tumour types.

Overexpression of cyclin D1 is associated with a variety

of cancer types and contributes to the development of

cancer. For example, overexpression of cyclin D1 has

been associated with the development of breast cancer.

These discoveries have led us to initiate a major

programme to discover and develop inhibitors of PKB

for the treatment of cancer.

Inhibition of PKB may

have therapeutic value

in those tumours that

exhibit abnormalities of

the PI3 kinase pathway

or overexpression of

cyclin D1 protein.

Drug discovery and

development – a

multidisciplinary programme

Drug discovery and development require input and

expertise from a number of different disciplines,

including basic research, high throughput screening,

medicinal chemistry, all the way through to the planning

and implementation of clinical trials. The PKB

programme reflects this multidisciplinary approach,

involving a number of teams from the Cancer Research

UK Centre for Cancer Therapeutics and the Section of

25


Structural Biology at The Institute, along with clinicians

from the Royal Marsden, and a collaboration with the

biotechnology company, Astex Technology Ltd.

In the Cancer Research UK Centre for Cancer

Therapeutics, the Analytical Technology and Screening

Team have carried out a high throughput drug screen

for inhibitors of the PKB protein using a library of

compounds. These can then be modified by medicinal

chemists in the Centre to generate more potent and

specific inhibitors of PKB – a process known as lead

optimisation.

Understanding the structure

of PKB provides novel

avenues for drug design

A major scientific breakthrough on the PKB project

came from Professor David Barford of the Section of

Structural Biology when his team solved the 3D

structure of the PKB protein (Figure 3).

This structural knowledge of PKB has aided in

our design of potent and selective inhibitors of PKB.

It has also allowed us, in collaboration with Astex

Technology Ltd, to pursue an alternative strategy for

the identification of PKB inhibitors, which uses

structure-based screening to identify drug fragments

that can then be optimised as lead compounds for

further chemical diversification.

Molecular pharmacology –

an important part of the

drug development process

Evaluating these potential new inhibitors of PKB is the

responsibility of the Cell Cycle Control Team. The key

objective here is to determine if the inhibitory

compounds are acting on PKB in the cancer cell. In

order to do this we treat cancer cells with the

compounds and then monitor PKB activity by looking at

the ability of PKB to signal to other proteins to promote

proliferation and survival.

Furthermore, given that we know PKB regulates the

level of the cell cycle protein cyclin D1 in the cell, we

also investigate whether the level of cyclin D1 has

decreased in the presence of the potential PKB inhibitor.

The development of these types of read-outs in cancer

cells is extremely important and a key objective is their

eventual use in clinical trials with patients so that we

can assess whether we are inhibiting the target, PKB, in

the patient.

Along with these studies in molecular pharmacology,

teams within the Centre with expertise in

pharmacokinetics and tumour biology then evaluate

these new compounds in laboratory assays. All this

information is then brought together and reviewed for

each compound so that a decision can be made about

whether further optimisation is required.

Figure 3.

The 3D crystal structure of

activated PKB. (Courtesy

of Professor David Barford,

Section of Structural Biology.)

Clinical input is vital for

the drug discovery and

development process

Phase I clinical trials

Once optimisation is complete the next stage is to

undertake a Phase I clinical trial with the PKB inhibitor.

This is carried out in the Phase I clinical trials unit at the

Royal Marsden.

Because the PKB inhibitor is a specific molecularly

targeted agent, it will be important to determine

whether we have inhibited PKB in the tumour of the

patient. Accordingly, an important objective for the PKB

inhibitor programme will be to be able to translate into

the clinic the various read-outs that have been

developed in the laboratory to measure PKB activity.


CANCER THERAPEUTICS/CANCER BIOLOGY

Clinical input is important

It is important to note that clinical input is important

throughout the whole drug discovery process. Indeed,

an initiating event for the PKB inhibitor programme was

a discussion with clinical colleagues about the types of

clinical issues that would need to be addressed in order

for a PKB inhibitor to be turned into an actual drug that

could be used to treat patients with cancer.

Here, an important issue for clinicians is how easy

will it be to administer a new drug to the patient, and

will it require multiple trips to the hospital. For the PKB

project this means investigating whether a PKB inhibitor

can be developed that can be given as a once-a-day pill.

The synergistic

interaction between

Institute scientists from

different disciplines,

clinical colleagues at

the Royal Marsden and

our partnership with

Astex Technology Ltd

is allowing the PKB

inhibitor programme

to progress rapidly

from gene to drug,

with the key objective

of providing faster

patient benefit.

The future for PKB inhibitors

At the start of this article we said that the treatment

of cancer patients is undergoing a major move

towards novel anticancer agents that specifically

target the molecular abnormalities of the cancer cell

itself. The PKB inhibitor programme is a reflection of

this move. Taking this one step further, it will be

important to determine whether a PKB inhibitor drug

will have most impact in those patients with

abnormalities in the PI3 kinase/PKB pathway. In this

way we can start to personalise cancer treatment for

maximum patient benefit.

A second potential application for a PKB inhibitor

drug in the clinic would be to combine this agent

with an existing anticancer drug. This could be a

conventional chemotherapeutic agent, such as a

taxane or carboplatin, or indeed another molecularly

targeted agent, for example gefitinib (Iressa). The

principle here is that combining a PKB inhibitor with

an existing drug will give superior patient benefit

compared to using either agent alone.

The ultimate objective

of the PKB inhibitor

programme is to offer

a personalised cancer

treatment to the patient

in the clinic.

27


CANCER THERAPEUTICS

Drug Development

Designer drugs for the cancer genome

We are now entering a new era of drug development:

very different from the cytotoxic drug era, in that we now

seek to develop highly specific drugs directed to distinct

molecular targets and hence with a much more selective

tumour action.

Designer drugs will be

more effective and

better tolerated than

cytotoxic drugs, which

damage normal dividing

cells as well as cancer

cells and therefore have

many side effects.

Stan Kaye

MD FRCP FRCR FRSE

FMedSci

Professor Stan Kaye is

Chairman of the Section

of Medicine and Cancer

Research UK Professor

of Medical Oncology at

The Institute of Cancer

Research. He is also Head

of the Drug Development

Unit at The Institute of

Cancer Research and

The Royal Marsden

NHS Foundation Trust

Paul Workman

PhD FMedSci FIBiol

Professor Paul Workman

is Director of the Cancer

Research UK Centre for

Cancer Therapeutics at

The Institute of Cancer

Research

Cytotoxic drugs

Historically, The Institute and the Royal Marsden played

leading roles in the design and development of many

of the cytotoxic drugs used for treating cancer

(eg melphalan, chlorambucil, busulphan, raltitrexed,

the platinum class of drugs).

Although this cytotoxic era of drug design and

development dates from the 1940s, cytotoxic drugs still

represent the mainstay of current drug treatment for

cancer. They are particularly effective in testicular cancer

and childhood leukaemia. However, cytotoxic drugs are

not so effective in advanced solid tumours that have

spread around the body.

Three key lessons learned from

the cytotoxic era

Drug resistance is frequent – whether intrinsic or

acquired during treatment.

Combinations or cocktails of drugs are generally

much more effective than single agents.

Although laboratory models are instructive, they

have limitations in predicting clinical usefulness.

The new era of drug

development

We are now entering a second era of drug

development: one that seeks to exploit our recent

knowledge of the molecular abnormalities, which result

from mutations of DNA, that drive cancer.

Oncogene addiction

Designer drugs will have a selective anti-tumour action

and will exploit what is known as oncogene addiction

(oncogenes are cancer genes). Oncogene addiction

means that cancer cells become dependent upon, or

addicted to, the very genetic abnormalities which drive

them. Thus, drugs that target the specific cell pathways

(see articles by Dr Michelle Garrett, p. 24 and Dr Pascal

Meier, p. 20, respectively) hijacked by cancer genes will

have a preferential action on malignant cells.

Previous lessons still hold good

However, the issues that we currently face are still

familiar. Firstly, we are seeing resistance develop to the

new generation of drugs. This often occurs not only by

further mutations in the oncogene target but also

because cancers are often driven by several, not just

one abnormality. We need to develop treatments that

tackle multiple genetic changes, and this, as with

current cytotoxic treatments, will involve the use of drug

cocktails. We also need to continue to refine and

improve our laboratory models of cancer.

Figure 1 summarises the new approach of designer

drugs for the cancer genome. Patients will be selected so

that their drug is matched to the precise genetic

abnormalities of their cancers. This requires the parallel

development of drugs and biomarkers for patient selection.


Examples of current projects

A variety of drug discovery projects are underway in the

Cancer Research UK Centre for Cancer Therapeutics.

(a)

Activation

of oncogenes,

eg by mutation or

overexpression

Inactivation

of DNA

repair genes

Deactivation

of tumour

suppressor genes,

eg by mutation

or deletion

Many are aimed at molecular targets that are mutated

or inappropriately active in cancer cells. A leading

example is BRAF, activated by mutation in around 70%

of melanomas and a smaller proportion of colorectal

and other cancers.

Genes

that support

oncogenic pathways,

eg those encoding

histone deacetylases

or Hsp90

Stimulation of

oncogenic signal

transduction

pathways

Targeting the BRAF oncogene

Following the discovery of BRAF as an oncogene by

Professor Mike Stratton (Section of Cancer Genetics) and

colleagues in the Cancer Genome Project, we rapidly

initiated a project to discover inhibitors of this particular

target. High throughput screening identified early leads

of possible chemical inhibitor molecules. These are now

being refined using the detailed 3D structure of the

BRAF protein obtained by Professor David Barford

(Section of Structural Biology) and Dr Richard Marais

(Cancer Research UK Centre for Cell and Molecular

Biology at The Institute). This project is a partnership

with the Wellcome Trust and Astex Technology Ltd.

Targeting the PI3 kinase PIK3CA oncogene

Rapid genome sequencing methods were also used to

discover mutations in another oncogene, the PI3 kinase

PIK3CA. We are developing inhibitors of this kinase in

collaboration with the spin-out company PIramed.

These inhibitors are very potent and selective for the

target and show promising activity in models of cancer,

including brain tumours. In her article (see p. 24),

Dr Michelle Garrett describes progress on a target in

the same cancer-causing pathway, AKT/PKB.

Drugs emerging from these programmes ideally will

be given in cocktails according to the nature of the

spectrum of underlying mutations in the particular cancer.

Targeting cancers that have multiple

molecular abnormalities

We use an alternative approach to tackle cancers with

multiple molecular abnormalities. Here, we target not

the individual oncogenes, but instead the support

systems upon which they are particularly dependent.

One of these is the so-called chaperone protein HSP90.

The job of this chaperone is to ensure that many

different cancer-causing proteins adopt the necessary

(b)

Developing

molecular markers

• Diagnosis

• Prognosis

• Proof of concept

• Pharmacodynamics

Phenotypic

hallmarks of malignancy

• Increased proliferation

• Inappropriate survival/decreased apoptosis

• Immortalisation

• Invasion, angiogenesis & metastasis

Cancer

Elucidating

the cancer kinome

• Discovery of all kinases involved in cancer

• Validation of these as drug targets

Personalised

cancer

medicine

shape they need to function. As with the BRAF and

AKT/PKB projects, we have identified inhibitors of

HSP90 by high throughput screening and have

determined the precise nature of the HSP90–inhibitor

molecular interaction in collaboration with Professor

Laurence Pearl (Section of Structural Biology). We are

now developing these inhibitors with our partners at

Vernalis and Novartis.

Developing

therapeutic agents

• Small molecule inhibitors

• Antibodies

• Antisense, RNAi, etc

Figure 1.

Genomics and

modern cancer

drug development.

(a) Different categories

of genes are involved

in cancer formation.

(b) The simultaneous

development of cancer

drugs and biomarkers

is required for

personalised cancer

treatment.

29


HSP90 inhibitors may

be particularly effective

because they

simultaneously block

the function of many

different cancer-causing

proteins, giving a

combinatorial effect.

Furthermore, cancer

cells appear to be

especially dependent

on HSP90.

Targeting the chromatin modifying

enzymes (CMEs)

Another set of targets – also expected to give a

powerful effect across many cancers – are the

chromatin modifying enzymes (CMEs). Chromatin is

the packaging material for DNA, and CMEs alter

chromatin to control gene expression. These processes

are deregulated in cancer. We are developing inhibitors

of several CMEs including histone deacetylases, histone

methyltransferases and Aurora kinases. These projects

are in partnership with Chroma Therapeutics Ltd.

Targeting the rarer forms of cancer

It is important that we also develop drugs for the more

rare cancers, caused by unusual genetic changes – all

the more because they will not be a priority for large

pharmaceutical companies since they have a low

commercial return as marketable products. Here, we are

working with colleagues in the Section of Paediatric

Oncology to develop drugs that will act on a type of

children’s cancer, known as rhabdomyosarcoma, which

is driven by a specific chromosomal translocation.

Clinical developments

From laboratory bench to the

patient’s bedside

A defining characteristic of the drug development

programme at The Institute and Royal Marsden is the

seamless transition of the most promising candidates

from the bench to bedside. This has required a major

commitment on the part of the Royal Marsden to

provide clinical facilities fit for purpose in the

demanding environment of early clinical trials in 2005.

This challenge has now been met by the opening of the

ward in the Drug Development Unit (now named the

Oak Foundation Drug Development Centre) at Sutton in

December 2004. With 16 beds (10 in-patient, 6 day

beds) exclusively for this purpose, and a fully dedicated

clinical research staff of doctors, nurses and others (over

40 in total) this facility is now well placed to play its

role as one of the world’s leading drug development

units in cancer. Figure 2 illustrates the increase in

activity in the Drug Development Unit over the past 2

years as well as the referral pattern over the past 12

months. All tumour types are represented, emphasising

the fact that the various molecular targets being

evaluated are present in most forms of cancer.


CANCER THERAPEUTICS

No. of patients

(a)

40

35

30

25

20

15

10

Figure 2.

(a) Activity in the

Drug Development

Unit at the Royal

Marsden over the

past 24 months

(2.5- to 3-fold

increase).

(b) Distribution

of tumour types in

patients referred to

the Drug Development

Unit in 2004.

5

0

Feb 2003

Mar 2003

Apr 2003

May 2003

Jun 2003

Jul 2003

Aug 2003

Sep 2003

Oct 2003

Nov 2003

Dec 2003

Jan 2004

Feb 2004

Month

Mar 2004

Apr 2004

May 2004

Jun 2004

Jul 2004

Aug 2004

Sep 2004

Oct 2004

Nov 2004

Dec 2004

Jan 2005

Patients on Trial Linear (Patients on Trial) New Referrals Linear (New Referrals)

(b)

L

M

K

N

O

A

J

B

I

C

D

E

F

G

H

A 1 % Cholangio-pancreatic

B 7 % Breast

C 6 % Colorectal

D 3 % Urinary

E 7 % Gynaecological

F 4 % Head & Neck

G 1 % Liver

H 10 % Lung

I 6 % Mellanoma

J 2 % Pancreas

K 29 % Prostate

L 4 % Renal

M 9 % Sarcoma

N 5 % Gastro-intestinal

O 6 % Other/unknown

Patients are referred

to the new ward from

all teams within the

Royal Marsden, and also

from a wide geographic

spread of other

oncologists. Great care

is taken to ensure that

appropriate patient

selection takes place.

Adding value to drugs from industry

Novel agents developed within the Centre for Cancer

Therapeutics form the core of our portfolio. However,

we are also conducting trials of a large number of

new drugs available from pharmaceutical companies –

generally aimed at molecular targets in which Centre

scientists have a particular interest. There are

approximately 20 open trials in the Drug Development

Unit (summarised in Table 1). While the majority of

trials involve evaluation of a single agent, we are also

committed to the concept that the activity of an existing

cytotoxic drug (eg carboplatin or a taxane) can be

enhanced by the addition of a novel drug with defined

inhibitory properties on relevant pathways.

31


Figure 3.

Effect of treatment with

17AAG in a patient

with malignant melanoma.

The CT scans on the lefthand

side indicate that

the melanoma (circled)

has stopped growing in

response to 17AAG. The

graph on the top righthand

side shows that

the levels of the drug in

the patient’s blood are

above those required

for blocking cancer cell

growth. The blots at the

bottom right-hand side

show the expected

molecular changes that

indicate that 17AAG is

having its desired effect.

Jul 2001

Feb 2003

17AAG µM

100

10

1

0.1

0.01

0.001

0 12 24 36 48

RAF-1

Time Hrs

HSP70

CDK4

GAPDH

Phase I trials

The prime purpose of Phase I clinical trials is to evaluate

the toxicity and body distribution (pharmacokinetics) of

a new drug. When dealing with novel molecularly

targeted agents, it is also crucially important that an

assessment is made of the ability of the drug to reach

and inhibit the specific target for which it was designed,

preferably in tumour cells (ie the proof-of-principle or

pharmacodynamic study). This aspect of our work

requires enhanced teamwork and involves colleagues in

radiology and pathology. In addition, the information

obtained from tumour biopsies also can be pivotal in

the evaluation of a new agent. An example is given in

Figure 3, illustrating the inhibition of the molecular

chaperone HSP90 – at well-tolerated doses – by the

HSP90 inhibitor, 17-allylamino 17-demethoxygeldanamycin

(17AAG). The particular patient involved,

with progressive metastatic melanoma, has had clear

evidence of sustained benefit from this treatment.

Phase II clinical trials (ie formal clinical trials to monitor

how effective a new drug is in patients) using 17AAG

in melanoma are now underway at the Royal Marsden.

Tumour efficacy

While not a primary endpoint of Phase I trials, we do

incorporate a careful assessment of tumour efficacy (ie

whether a new drug has an effect in shrinking or

eliminating tumours) in all patients. There is no doubt

that responses are now being seen regularly with a

number of the new drugs in our portfolio. These include

clear tumour shrinkage in patients with non-small cell

lung cancer given an m-TOR inhibitor (m-TOR is a key

signal in the PI3 kinase/PKB pathway), and also a pan-

ERBB inhibitor, as well as prolonged tumour

stabilisation in patients with sarcoma treated with a

broad spectrum or pan-kinase inhibitor.

Hot areas

An important health care goal as the cost of drugs

escalates is the rational selection of patients most likely

to benefit from a particular treatment, as well as

identifying which patients (often the majority) should

not be treated with ineffective and costly drugs. Here,

we predict that appropriate patient identification, using


CANCER THERAPEUTICS

molecular diagnostics, will increasingly feature alongside

new drug development. This will apply equally to the

use of new drugs both as single agents and in novel

combination schedules.

Examples include the key observations linking

mutations of the epidermal growth factor receptor

(EGFR) to the likelihood of a response to EGFR

inhibitors, gefitinib (Iressa) and erlotinib (Tarceva) in

patients with lung cancer.

In addition, Professor Mike Stratton, who leads the

Cancer Genome Project in the UK, has recently

discovered mutations predicted to activate the

ERBB2 receptor in patients with lung cancer

(adenocarcinoma). This opens up the exciting

possibility of being able to detect a further specific

molecular target that will predict response to new

agents in this disease. This approach is being actively

developed within the Royal Marsden Lung Unit.

Several of the agents under development in our

programme target the PI3 kinase/PKB pathway.

Here, patient selection is also important, in that

tumours bearing mutations of the important tumour

suppressor gene, PTEN, may be particularly

susceptible to this approach. This also applies to

tumours with activating mutations of PI3 kinase

itself (specifically PI3KCA which encodes the P110

·-subunit of the protein molecule). Examples include

glioblastoma, prostate cancer and endometrial

cancer as well as certain patients with colorectal,

gastric and breast cancer. This will certainly form an

important part of our strategy as agents acting on

these targets enter the clinic over the next few years.

A reasonable

assumption underlying

the development of

molecularly targeted

therapy is that new

agents will have their

maximum impact in

selected patients whose

cancers possess the

molecular targets

against which the drug

is designed to act.

Table 1. Novel agents in current or recent Phase I trials in the Drug Development Unit

Drug

Mechanism factors

ZD6126

Antivascular agent

RAD 001

mTOR inhibitor

LAQ 824

Histone deacetylase inhibitor

PXD-101

Histone deacetylase inhibitor

Omnitarg/Taxotere

Cytotoxic, plus anti-ErbB monoclonal antibody

BIBF 1120

Angiogenesis inhibitor (VEGFR, PDGFR, FGFR)

BAY 43-9006

Multi-kinase inhibitor

CHIR 258

Angiogenesis inhibitor (VEGFR, PDGFR, FGFR)

ZK 30479

Combined cell cycle (CDK) inhibitor and

angiogenesis (VEGFR) inhibitor

Carboplatin/ET743

Cytotoxic, plus DNA minor groove binder

ES 285

Rho kinase inhibitor

MG 98

DNA methyl transferase inhibitor

HGS-ETR2

Death receptor antibody (extrinsic apoptosis)

Reolysin

Oncolytic reovirus

Chr 297

Aminopeptidase inhibitor

BIBW

Pan-ErbB inhibitor

17 DMAG HSP90 (molecular chaperone) inhibitor

CP751/Taxotere

Cytotoxic plus anti IGF-1R monoclonal antibody

33


CANCER THERAPEUTICS

Haemato-Oncology

Myeloma research:

novel therapeutic approaches

Approximately 3,500 new cases of myeloma are diagnosed

in the UK each year. The majority of cases occur over the

age of 60 years, but 20–30% of cases still occur in the

40–60 year age group.

Gareth Morgan

PhD FRCP FRCPath

Professor Gareth Morgan is

Professor of Haematology

at The Institute of Cancer

Research and Head of the

Haemato-Oncology Unit at

The Royal Marsden NHS

Foundation Trust

Haemato-Oncology

The Section of Haemato-Oncology at The Institute and

the Haemato-Oncology Unit at the Royal Marsden are

committed to improving the outlook for patients with

myeloma by developing novel therapeutic approaches

based on a sound knowledge of the biology of the

disease. In order to do this we have developed an

integrated service, which combines laboratory-based

research looking at the characteristics of myeloma cells,

with a comprehensive clinical service covering

chemotherapy, radiotherapy, stem cell transplantation

and new drugs.

The hope is that over

the coming years we will

be able to individualise

patients’ therapy based

on our laboratory studies,

leading to an improved

outlook and survival for

patients with an associated

decrease in side effects

and improvement in

quality of life.

Myeloma background

Myeloma is a malignant blood cancer caused by the

uncontrolled growth of plasma cells. These are a type

of white blood cell that produce antibodies to fight

infections. In myeloma, malignant plasma cells produce

large amounts of abnormal antibodies.

The range of clinical effects of myeloma include

bone marrow suppression resulting in an increased

susceptibility to infection, lytic bone lesions (Figure 1),

the production of a paraprotein, spontaneous fractures,

bone pain and renal failure. These clinical effects occur

because of the presence of a malignant plasma-cell

infiltrate within the bone marrow, producing a single

variety of immunoglobulin called a paraprotein.

Currently a cure for myeloma is not possible, but

with the introduction of targeted treatment strategies

the possibility of turning this disease into a chronic

disorder that can be managed over many years is

becoming a reality.

The current world standard treatment for myeloma

is an autologous (ie from the same person) stem cell

transplant for patients who are able to tolerate it – a

treatment method originally pioneered at the Royal

Marsden. However, the majority of patients eventually

relapse following this treatment and so there is a need

to integrate novel therapies into standard treatment

strategies. New therapies need to be targeted, based

on an understanding of the biology of myeloma.

Myeloma biology

Myeloma plasma cells and their bone

marrow environment

Myeloma plasma cells exist in the bone marrow in

a complex environment where there are intricate

biological interactions occurring. It is widely recognised

that there are important positive feedback loops in the

bone marrow that favour the survival of myeloma

plasma cells, which involve cytokines.

Cytokines are messenger molecules that regulate

cell function. Important cytokines in myeloma include

IL6, TNF·, IGF, and VEGF – all of which now can be

specifically targeted with drugs. Some of the new drugs

being introduced into the clinic can target these

multiple cytokine feedback loops and have proven to


e very useful. Examples include thalidomide, as well its

more potent derivative lenolidamide (Revlimid), which is

associated with a more favourable side effect profile.

Other drugs such as atiprimod, which also inhibit

multiple cytokine loops, may also prove to be important.

Osteoclasts – the destroyers of bone

Cellular interactions also occur in the bone marrow

between myeloma plasma cells and other cells called

osteoclasts. Osteoclasts are the cells that break down

bone. When osteoclasts are activated by osteoclast

activating factors, which are secreted by the malignant

myeloma plasma cells, this then leads lead to bone

resorption and raised blood calcium levels

(hypercalcaemia). This interaction can be targeted by the

bisphosphonate class of drugs, as well as drugs that target

what is called the RANK ligand/osteoprotegerin pathway.

This provides a novel strategy for the therapeutic inhibition

of myeloma plasma cells as well as osteoclasts.

Genetic studies and

clinical outcome

Single nucleotide polymorphisms (SNPs)

We are aiming to look at the genetic make-up (ie the

DNA sequence) of thousands of myeloma patients to try

and determine why it is that patients develop myeloma,

and also to understand why patients respond differently

to therapy and why certain patients develop side effects

from therapy. Within the DNA sequence, alterations can

occur to a single chemical base (these chemical bases

are called nucleotides). These alterations are called

single nucleotide polymorphisms (SNPs) and within the

structure of a gene there are a number of different SNPs

that can alter the function of the gene.

Having obtained DNA from a mouth swab or blood

sample we are able to detect up to 10,000 SNPs in a

single experiment, and then go on and correlate the SNP

pattern with the patients’ clinical experience. We are

using this technique in current research to determine

why up to 30% of patients experience peripheral

neuropathy side effects (ie side effects due to damage

to the peripheral nerves that go out from the brain and

spinal cord to the muscles, skin, internal organs and

glands) with thalidomide or bortezomib (Velcade).

Genetics and patient outcomes

Although there are a number of prognostic staging

systems (ie methods for placing a patient into a

particular type of clinical category) that can separate

myeloma patients into groups which are likely to have

different outcomes, most of these staging systems have

been around for many years and they neither

incorporate recent developments in myeloma science,

nor are they used regularly by physicians for deciding

on treatment options.

As part of a current trial (Myeloma IX) we are

performing a comprehensive genetic analysis of patient

myeloma cells, linking the findings with response to

treatment and survival. The ultimate aim is to identify a

series of genes that can predict patients’ response to

therapy. In particular, we wish to identify patients who

will respond poorly to standard treatments so that novel

treatment approaches can be offered early to this

subset of patients.

Genetic studies and

new therapies

Oncogenes

It is known that the integrity of the DNA and RNA

within myeloma plasma cells is damaged, and recent

Figure 1.

Lytic bone lesions,

which are readily seen

on plain skeletal X-rays,

are a major problem in

multiple myeloma,

where they cause back

pain and increase the

risk of skeletal fracture.

The lesions appear as

darkened areas in the

bone. At the Royal

Marsden we are

exploring the use of

new imaging

modalities, such as

PET scanning.

35


studies have suggested that patients with different

chromosomal characteristics have different prognoses.

Characterising these differences further is important

because identifying the damaged genes will allow us to

target therapies to these genes. One important strategy

to identify deregulated genes relies upon the

identification and targeting of oncogenes (genes that

have been deregulated, often because of recurrent

chromosomal rearrangements).

Oncogenes are regularly found in chromosome 14.

An example is the oncogene FGFR3 (fibroblast growth

factor receptor 3), which is deregulated by genetic

translocation (where a section of DNA in the

chromosome breaks but is then reinserted in the wrong

place). The FGFR3 oncogene occurs in 15% of myeloma

patients. Our previous studies have characterised where

the FGFR3 translocation occurs (in position 4;14) and

also demonstrated that cases with this translocation

have a distinct gene expression profile.

We are now investigating

how to specifically target

the FGFR3 oncogene in

the clinical environment

using small molecule

tyrosine kinase inhibitors.

Initial results, based on

pre-clinical and clinical

data suggest this may

prove to be an excellent

treatment option for

well-defined subsets

of patients.

Another recurrent chromosome abnormality – a

translocation in position 11;14 – deregulates a group of

proteins called D group cyclins, which are involved in

helping regulate cell growth and cell division. Targeting

gene deregulations associated with D group cyclins may

be a therapeutic option for 30–40% of myeloma patients.

Defining new biologically

relevant targets

Proteosome inhibition

Other important therapeutic advances have come from

the study of the molecular pathogenesis of myeloma

(Figure 2). The current, most clinically relevant of these

therapeutic advances, is proteosome inhibition using

bortezomib. The proteosome is an important intracellular

organelle, which degrades signalling molecules in a

structured fashion, allowing the complex inter- and

intracellular cross-talk that is essential for either normal

or malignant cell activity. It is possible to reversibly

inhibit the proteosome, without causing excess toxicity,

and it has now been shown that malignant plasma cells

can be selectively killed in this way.

Important targets of proteosome inhibition include

the NFÎB/ÎIB complex and cell signalling molecules.

In our laboratory programme we are trying to

develop more such molecules, selectively targeting

other pathways, to give us further therapeutic

options aimed at long-term control of the myeloma

clone. In this context, an important plasma-cell

specific pathway, which may set plasma cells apart

from other cells within the body, is their ability to

produce paraprotein. The cellular response within the

plasma cells enabling them to produce these

paraproteins requires an adaptive change and this

can be specifically targeted. With this in mind, we

are specifically investigating the role of the HSP90

protein inhibitor, a drug developed in The Institute.

By targeting different areas in the plasma-cell

specific process we hope to increase the effects of

the HSP90 inhibitor. Interestingly, based on its mode

of action, bortezomib is likely to work synergistically

with HSP90 inhibitors. It seems likely that many new

agents will work better in combination and we are

specifically working in the laboratory to develop

model systems for the evaluation of such

combinations, which may then be taken forward into

the clinical setting.


CANCER THERAPEUTICS

Integrating new drugs into the

clinical treatment strategy

In these ever changing times we feel

Chromosome 14 translocations

Early

Late

t(4;14) FGFR3/MMSET

t(8;14) MYC

t(6;14) MUM1

that it is important to integrate some of

t(11;14) cyclin D1

the newer drugs into clinical treatment

strategies quickly. Drugs which have

t(14;16) CMAF

Immortalisation Independent growth of malignant plasma cell

been shown to be effective in recent

years such as thalidomide, bortezomib

and lenolidamide are being integrated

into our routine practice, but importantly

we are also running a number of

investigational protocols, based on

Increasing genetic instability 13q- Activating mutations p53 and RAS

laboratory data, combining these

targeted drugs with standard

chemotherapies to try and further improve

Normal

plasma cell

MGUS Myeloma Plasma cell

leukaemia

response rates and remission durations.

The future

As part of our Phase I trial commitment we are also

Figure 2.

A molecular model of

investigating the potential therapeutic effects of a We are making excellent progress in our understanding multiple myeloma.

number of new drugs. Importantly, all of these have of the use of novel small molecule chemotherapeutic

Models of myeloma are

based on a clinically

been shown to be effective in laboratory studies, but approaches and how to integrate advances in these defined multi-step

pathogenesis, where a

have not been tested previously in cancer patients. areas with standard treatments.

normal plasma cell is

Therefore the emphasis of these trials is to investigate Over the next few years we expect to see significant

envisaged to transform

into a pre-malignant

the drugs’ potential anti-myeloma effects, whilst closely advances in the quality of life and survival of patients stage (MGUS), which

then transforms to

monitoring for side effects. It is hoped that by

with myeloma. Our combined clinical and laboratory myeloma. At the endstage

performing trials such as this within the Royal Marsden organisation will directly facilitate the transition of new of the disease,

these myeloma cells no

that we can make quick and efficient steps forward in laboratory developments into the clinic, so that patients longer remain located

within the bone marrow

making useful and effective drugs more widely available can benefit at the earliest possible stage.

and can now be found

for patients.

in the peripheral blood.

The initiating events for

myeloma are thought to

involve chromosomal

Modulating the

translocations, whilst

later events involve

immune system

mutations of either RAS

or p53 oncogenes,

together with other

as yet ill-defined

genetic lesions.

We have shown that thalidomide can enhance the

immune system – in particular natural killer (NK) cells

– which work against the myeloma plasma cells. These

laboratory and targeted treatment approaches are

complemented by our transplant programme, which is

aimed at using dual autologous (ie same person) and

mini-allogeneic (ie different people) transplants to both

stabilise the malignant clone and then to introduce

donor T-cells in an environment where it is possible to

benefit from the graft versus myeloma effect. This T-cell

immunomodulation is relevant clinically and provides a

way of safely performing an allogeneic transplant in

older patients.

We firmly anticipate

that myeloma will

become a chronic

disease, which can be

managed long-term

without impacting

significantly on the

quality of life of patients.

37


CANCER THERAPEUTICS

Colorectal

Cancer

New therapies for colorectal cancer

Colorectal cancer is one of most common cancers

worldwide and in the UK alone, over 35,000 new

cases are diagnosed each year.

Stages of colorectal cancer

Improving outcomes

after surgery

The use of chemotherapy following surgery, a procedure

known as adjuvant therapy, is well established for

patients with colorectal tumours involving local lymph

nodes (Duke’s C cancer). With Duke’s C cases, adjuvant

therapy has been shown to reduce the chance of

relapse and improve survival following surgery to

remove the primary colorectal tumour. In contrast, for

those patients with no regional lymph node involvement

(Duke’s B cancer), the role of adjuvant chemotherapy

has been far less clear. However, data from two large

randomised Phase III trials, QUASAR (UK led) and

MOSAIC (European) now indicate that adjuvant

chemotherapy is beneficial for Duke’s B patients.

David Cunningham

MD FRCP

Professor David

Cunningham is a

Consultant in Medical

Oncology and Head of the

Gastrointestinal Unit at The

Royal Marsden NHS

Foundation Trust

A significant number of patients present with early

stage colorectal cancer and are suitable for

potentially curative surgery. However, a proportion of

these patients are at risk of cancer recurrence and

strategies to identify these subgroups and develop

preventive therapeutic strategies have been a key

area in attempting to improve outcomes from the

disease.

Approximately 25% of patients with colorectal

cancer will present with advanced disease or

develop metastatic disease despite earlier therapy.

The development of effective treatments for this

group of patients is also of paramount importance.

The Royal Marsden

Gastrointestinal Unit

has a critical role in

contributing to, and

in leading research

into the treatment of

colorectal cancer, both

in the national and

international arenas.

Bolus versus a continuous infusion of

adjuvant chemotherapy

Currently, the standard length of time of adjuvant

chemotherapy using bolus (ie repeated short injections)

5-fluorouracil (5FU) is 6 months. However, there is

debate over the optimal duration of treatment and on

whether or not adjuvant chemotherapy given as a

constant continuous infusion might provide better

suppression of the growth of cancer cells. This question

has been addressed in the SAFFA randomised Phase III

multicentre UK study. The SAFFA study was designed

and conducted by the Gastrointestinal Unit, and

compared whether 3 months of continuous infusion of

5FU was equivalent to 6 months of bolus 5FU in

patients following surgery for colorectal cancer. The

results, presented and discussed at the 2004 American

Society for Clinical Oncology (ASCO) annual meeting,

indicated equivalence between the two treatments and

importantly, that shortening the duration of

chemotherapy with infused 5FU did not compromise

patient outcomes.

An analysis of the Duke’s B patients in the SAFFA

study has also been undertaken. Duke’s B patients, with

at least one of a defined set of risk factors, who are

treated with adjuvant chemotherapy, are predicted to

have a poorer outcome than patients who do not have

at least one of a defined set of risk factors. Such

knowledge may help select patients from this group for

adjuvant therapy.


The duration of

adjuvant chemotherapy

is an important area of

research and further

studies are being

designed worldwide

to address this issue.

Therapy before surgery

Treatment of potentially operable tumours before

surgery has advantages in certain groups of patients.

Advances in surgical techniques, including total

mesorectal excision, have improved rates of relapse in

rectal cancers but further progress is needed. The

EXPERT study designed and undertaken by the

Gastrointestinal Unit, aims to investigate the use of preoperative

therapy to reduce the rate of relapse in rectal

cancers. Here, high definition magnetic resonance

imaging (MRI) has been used to identify patients with

operable rectal cancer that displays features indicative

of high-risk relapse. These high-risk relapse patients

have been treated using combination chemotherapy

(capecitabine and oxaliplatin), followed by

chemoradiotherapy and then subsequent surgery. This

approach has resulted in a high rate of tumour shrinkage

and successful surgery and the results of the study were

presented at the 2005 ASCO Gastrointestinal Symposium

held in Miami, USA, in January.

Liver metastases in colorectal cancer

The liver is the most common site for secondary spread

from colorectal cancer and in a significant proportion of

patients is the only organ involved. A small proportion

of patients have liver metastases that can be removed

by surgery, a strategy known to improve disease-free

time and which may potentially result in cure.

However, it is recognised that chemotherapy,

particularly including oxaliplatin, may improve the

operability of liver metastases and therefore further

improve outcomes. Nevertheless, there are currently no

prospective data on this issue. At the Royal Marsden,

the Gastrointestinal Unit is running a Phase II nonrandomised

study of capecitabine (an oral pro-drug

of 5FU) plus oxaliplatin, a highly active chemotherapy

combination in colorectal cancers, pre- and post-liver

resection, and will eventually provide some of the

first data with this drug combination in this

important setting.

Making progress with

new drugs

The emergence of several new drugs – including

capecitabine, oxaliplatin and irinotecan – in the last

decade has had a great impact on the treatment of

colorectal cancer. Various combinations, schedules and

use as first line and salvage therapies have improved

survival and quality of life for sufferers of the disease.

However, new approaches are desperately needed to

achieve further improvements in care.

As we begin to gain a

greater understanding

of the biological

processes governing

the development of

colorectal cancer, new

therapeutic targets have

been identified and

exciting new treatments

for colorectal cancer

successfully developed.

39


Figure 1.

Targeting the epidermal

growth factor receptor

(EGFR). Cetuximab

(Erbitux) binds to the

external domains of the

EGFR, whereas gefitinib

(Iressa) binds to the

internal domains of the

EGFR. Either molecule

can therefore block

activation of the EGFR,

interfering with the

subsequent function

of the cancer cell.

External

domains of

the EGFR

Cell

membrane

Internal

domains of

the EGFR

Gefitinib

Triggering the EGFR of cancer

cells can result in subsequent:

• cell growth

• cell survival

• invasion and tumour metastasis

• tumour blood vessel growth

Cetuximab

Cetuximab (Erbitux) – an inhibitor of the

epidermal growth factor receptor

The epidermal growth factor receptor (EGFR) is a cell

membrane receptor whose activation is thought to

contribute to cancer development and progression.

EGFR has a portion of the molecule that is outside the

cell and a portion within the cell (Figure 1). Cetuximab

is a monoclonal antibody that targets the outer portion

of EGFR, thereby blocking its activation (Figure 1). This

has generated a huge amount of interest in colorectal

cancers known to overexpress EGFR. On the basis of a

pivotal randomised Phase II European trial led by

Professor Cunningham, cetuximab was licensed for use

in EGFR positive, irinotecan-refractory colorectal cancer

in June 2004.

The trial randomised patients with colorectal cancer

resistant to irinotecan therapy (many of whom were

heavily pre-treated) between irinotecan plus

cetuximab or cetuximab alone treatment options.

Responses to therapy were seen in both groups, with

a larger benefit seen in the irinotecan plus

cetuximab group (response rate of 23%). Cetuximab

was therefore able to reverse resistance to prior

irinotecan chemotherapy in a proportion of patients

and provide a further treatment option to those

patients for whom further therapy is extremely

limited. An example of a response to cetuximab

monotherapy is shown in Figure 2.

The study was published in the New England Journal of

Medicine in July 2004 and has served as a catalyst for the

implementation of several new Phase II and III studies of

cetuximab in combination with chemotherapy agents

both in the first and second line treatment of colorectal

cancer. It has provided a significant contribution to

developing effective therapies for patients with pretreated

cancer, a group that is assuming greater

importance. Furthermore, other ways to target EGFR are

in development; gefitinib (Iressa) is a drug that acts on

the inner portion of the EGFR (Figure 1) and a trial

combining this drug with chemotherapy in patients with

colorectal cancer has recently been completed in the

unit. The results are awaited with interest.

Bevacizumab: interfering with the blood

supply to tumours

For decades we have known that tumours are able to

stimulate their own blood supply in order to continue to

grow, a process called tumour angiogenesis. The blood

supply is often chaotic and inefficient in delivering

oxygen to the tumour. The lack of oxygen further

stimulates new tumour blood vessel growth. One of the

main stimulants of angiogenesis is a small molecule

called vascular endothelial growth factor (VEGF).

Bevacizumab is a drug that targets VEGF and therefore

interferes with the growth of new vessels.

A large Phase III study in the USA published last

year indicated that adding bevacizumab to

chemotherapy in patients receiving treatment for the

first time resulted in improved response to treatment

and survival. The Gastrointestinal Unit is currently

recruiting patients with colorectal cancer into several

international trials of bevacizumab and chemotherapy

to further characterise potential benefits of this exciting

new therapy.


CANCER THERAPEUTICS

Future directions

The new targeted therapies, including cetuximab and

bevacizumab are very much in the spotlight and the next

year is likely to see the development of these treatments

in both advanced and early stage colorectal cancer. The

Gastrointestinal Unit aims to be at the forefront of this

research and a number of projects utilising these and

other novel agents are in development:

A multicentre European study of cetuximab in

combination with chemotherapy and radiotherapy as

curative treatment for rectal cancers is planned and

will be led and managed by the Gastrointestinal Unit.

Increasingly, combining targeted agents in an

attempt to knock out several cancer mechanisms

simultaneously will be a key area of research.

It is also crucial to identify which patients are most

likely to respond to these therapies on the basis of

individual tumour characteristics, in order that

therapeutic management can be tailored to

the individual.

The identification of appropriate patients for therapy

and inclusion in clinical trials is vital to the continuing

progress in clinical research made by the

Gastrointestinal Unit. Here, we acknowledge the

willingness of our patients to participate in clinical trials

in colorectal cancer. We continue to aim to provide them

with an ongoing and strong multidisciplinary

environment and a commitment from all members of

the research team.

Baseline

Same patient after 6 weeks of cetuximab chemotherapy

Figure 2.

Response of liver

metastases (indicated

by white arrows) to

cetuximab in a patient

with advanced

colorectal cancer.

Professor David

Cunningham and

the medical team

41


CANCER THERAPEUTICS

Skin Cancer

Melanoma: our understanding of the

disease increases but prevention is still

the best medicine

Excessive exposure to ultraviolet (UV) radiation is the

major risk factor for melanoma, especially burning and

blistering in childhood and teenage years. Most early

melanomas have a characteristic appearance and initially

remain localised. For these reasons the disease is

amenable to prevention and early diagnosis.

J Meirion Thomas

MS FRCP FRCS

Mr J Meirion Thomas is a

Consultant Surgeon in the

Skin Cancer and Melanoma

Unit at The Royal Marsden

NHS Foundation Trust

Melanoma is the least

common but most dangerous

skin cancer

Despite the fact that melanoma is the least common

skin cancer, its incidence is nevertheless rising faster

than any other cancer.

In the UK, the incidence of melanoma approximately

doubles every 10–15 years.

Melanoma is the third most common cancer in

women under 40 years of age and the second most

common cancer in males under 40 years of age.

There are 7,000 cases of melanoma diagnosed every

year in the UK and 1,600 deaths, accounting for 1%

of all cancer deaths.

Prognosis and depth of

penetration of a melanoma

into the skin

Thereafter, there is a linear relationship between tumour

thickness and risk of recurrence. For example, the risk of

recurrence over a 5-year period at 2 mm is 15–20%,

and at 5 mm there is a 60–70% risk of recurrence.

Recent advances in best

practice for melanoma surgery

For some years now there has been debate about what

margin of normal-looking skin should be removed when

poor prognosis melanomas (as defined by a tumour

thickness of at least 2 mm) are excised. The issue has

been addressed recently in a study carried out by The

Institute and the Royal Marsden.

The study compared removal of a 1 cm as opposed

to a 3 cm radius of normal-looking skin around the

melanoma. A total of 900 patients were entered into

the trial, half into the 1 cm margin and half into the 3

cm margin group.

The trial was coordinated from The Institute’s Section

of Clinical Trials (Gill Coombes, Senior Clinical Trials

Manager; Trial Statisticians, Roger Ahern and Judith

Bliss). Previously, four randomised controlled trials of

good prognosis melanoma had failed to show any

advantage for wider excision. Our trial was the first to

investigate poor prognosis melanoma. The study, which

was published in the New England Journal of Medicine,

found that patients with a 1 cm margin were more likely

to have a recurrence than those with a 3 cm margin.

Follow-up of patients is continuing in order to detect

any influence on overall survival.

About 70% of melanomas are of the superficial

spreading variety (Figure 1). These have characteristic

physical signs (irregular border, differential pigmentation

and central depigmentation). There is a good prognosis

for the superficial spreading variety of melanoma, for a

variable period of time, possibly several years, before it

transforms into its penetrating and dangerous

counterpart. The prognosis of a melanoma is determined

by its depth of penetration into the skin. This is known

as Breslow tumour. If the tumour thickness is less than

0.76 mm, then the risk of recurrence is extremely low.


Figure 1.

Superficial spreading

melanoma.

This is the first trial to

have ever shown that

the amount of normallooking

skin removed

from around a

melanoma influences

the patient’s outcome.

The findings are

important because they

suggest that a small

number of patients with

thick melanoma may be

cured by a wider

margin of excision.

Recent advances in systemic

therapies for melanoma

Under the direction of Professor Martin Gore, Head of

the hospital’s Skin Cancer and Melanoma Unit, the Royal

Marsden and The Institute have made a significant

contribution to the development and investigation of

systemic therapies for melanoma. The Unit, together with

colleagues at The Institute, performed the first cancer

gene therapy trial in the UK, and over the last 10 years

has also been one of the leading recruiters into

European Organisation for Research and Treatment of

Cancer (EORTC) trials investigating the use of interferon

in metastatic melanoma.

Currently, an exciting project, led by Dr Tim Eisen

(Section of Medicine) and Dr Richard Marais (Cancer

Research UK Centre for Cell and Molecular Biology) is

underway to exploit known genetic abnormalities

present in 85% of melanomas. These abnormalities

affect a molecular signalling pathway in melanoma cells

(the RAS/RAF pathway) and a number of drugs are now

in development to try to block this pathway.

Recent advances in the

treatment of in-transit

metastatic melanoma

The Royal Marsden has also made a significant

contribution towards the treatment of in-transit metastatic

melanoma. Commonly, melanoma disseminates via

lymphatic vessels and tumour cells can become trapped in

these en route (ie in-transit) between the primary tumour

site and the regional lymph nodes. This results in the

development of multiple tumour nodules within the skin

and subcutaneous tissues, which can ulcerate and can

cause morbidity to an extent that amputation may

become necessary for palliative treatment.

Treatment of these tumour nodules within the skin

by carbon dioxide laser vaporisation is a technique that

43


The Royal Marsden is

the only hospital in

England and Wales that

offers HILP using TNF·.

Figure 2.

Pre- and post-carbon

dioxide laser vaporisation.

was developed and evaluated exclusively at the Royal

Marsden, and is now in widespread use. Regional

disease in most patients can be controlled by carbon

dioxide laser vaporisation treatment three or four times

per year, in a daycare setting (Figure 2).

However, as the disease accelerates, a proportion of

patients then will require treatment by what is called

hyperthermic isolated limb perfusion (HILP). Using HILP,

the blood circulation to a tumour-affected limb is first

stopped using a tourniquet, and the isolated limb then

perfused with the drug melphalan (originally synthesised

at The Institute) together with recombinant human

tumour necrosis factor alpha (TNF·) (Figure 3). However,

because of the profound systemic toxicity of TNF· on the

normal cardiovascular circulation, it is essential to have a

leak-monitoring system in place that will rapidly detect

any leakage of TNF· across the tourniquet, so that HILP

can be terminated if necessary. In order to achieve this,

the radioactive isotope 99m Tc, attached to human serum

albumin, is injected into the perfusion mixture as soon as

the isolated limb circulation is established and any

leakage of 99m Tc that then occurs across the tourniquet

can be detected real-time using a radiation detector

positioned over the patient’s heart. This operation

involves cooperation between surgeon, anaesthetist,

perfusionist and physicist.

The controversy of selective

lymphadenectomy –

a 113-year-old theory

that remains unproven

A major and controversial area of current melanoma

research was begun by Dr Herbert Snow, who was a

surgeon at the Cancer Hospital, Brompton (now the

Royal Marsden) between 1876 and 1905. Dr Snow

published a pivotal paper in The Lancet on 15th October

1892 entitled ‘Melanotic cancerous disease’. In his

paper, Dr Snow gives a remarkably accurate account of

the natural history of melanoma and its prognosis

according to stage. He made the observation that when

patients presented with bulky metastatic nodal disease,

they invariably died of distant spread. He therefore

proposed the operation of anticipatory lymphadenectomy

and stated the following: ‘It is essential to remove

whenever possible those glands which first receive the

infected protoplasm and bar its entrance into the blood

before they undergo increase in bulk.’

Dr Snow’s intuitive extrapolation of early nodal

surgery became known as elective lymph node dissection

(ELND) and in 1992 evolved into the operation of

selective lymphadenectomy, which is regarded as

‘standard of care’ in the USA and other countries.

Selective lymphadenectomy is based on the concept

of the sentinel node (defined as the first drainage lymph

node involved by the metastatic process). The sentinel

node can be reliably identified by a combination of dye

and radioactive colloid injected into the skin at the site

of the primary tumour. If the sentinel node is positive for

early metastatic disease the patient is advised to

undergo lymphadenectomy.

The problem is that 113 years later on, Dr Snow’s

theory remains unproven.


CANCER THERAPEUTICS

Four randomised

controlled trials of

ELND showed no

overall survival

advantage and the

international trial

on selective

lymphadenectomy

will not be published

until 2006.

Pump

Venous

blood

Oxygen

Tourniquet

300mm Hg

Arterial

blood

Heater

Drugs

Figure 3.

Hyperthermic isolated

limb perfusion.

To add to the controversy, two publications from the

Skin Cancer and Melanoma Unit have suggested an

iatrogenic complication (ie a complication resulting

from the treatment itself) of selective lymphadenopathy

– namely an increased incidence of in-transit disease.

The hypothesis is that synchronous wide excision of

the primary tumour and local lymphadenopathy means

that the normal lymphatic flow is disturbed

and obstructed so that melanoma cells become

entrapped within lymphatic channels – and there they

will progress to form tumour nodules in the skin and

subcutaneous tissue.

However, there is a positive corollary to the above

warning. Dr Eleanor Moskovic in the Department of

Radiology at the Royal Marsden has shown that elective

inguinal node dissection for squamous carcinoma of the

vulva can be replaced by ultrasound surveillance and

ultrasound-guided fine-needle aspiration cytology when

the nodes look suspicious. Selective lymphadenectomy

can be undertaken based on the identification of nodal

deposits as small as 4 mm. We have now started an

identical surveillance programme for melanoma after

wide excision.

Where does this leave us

The future

Despite step-by-step improvements in our

understanding of melanoma and its treatment, the

reality is that this devastating disease is largely brought

about by excessive exposure to UV radiation, particularly

during childhood and teenage years. Melanoma is

essentially a preventable disease, and as such, priorities

for the future should include a national programme of

public education about the disease, as well as a

national programme of early diagnosis.

Dr Elanor Moskovic

and Mr Meirion Thomas

evaluate tracer

distribution in a patient

45


IMAGING RESEARCH & CANCER DIAGNOSIS

Nuclear Medicine

Rapid advances in the diagnosis

and treatment of cancers

The development of combined positron emission

tomography (PET)/computed tomography (CT) scanners

is a major step forward in the detection of cancer and

in evaluating response to treatment.

Gary Cook

MSc MD FRCP FRCR

Dr Gary Cook and Dr Val

Lewington are Consultants

in Nuclear Medicine and

PET at The Royal Marsden

NHS Foundation Trust

Val Lewington

MSc FRCP

Two key areas of rapid

development in

nuclear medicine

Nuclear medicine involves the use of radioactive isotopes

in the diagnosis and treatment of many diseases but has

an especially important role in oncology. Whilst many

diagnostic and therapeutic nuclear medicine techniques

are used in day-to-day routine patient management

there are two key areas that have shown rapid recent

development, with evidence of improvement in patient

management and care.

Positron emission tomography (PET) scanning uses

radiopharmaceuticals such as 18 F-fluorodeoxyglucose

(FDG) to detect abnormally increased glucose

metabolism in malignant cells to help to pinpoint

cancer more sensitively and to monitor treatment

more effectively. The most recent advance in this

modality is in the development of combined PET/CT

scanners that can monitor tumour function (PET) as

well as detect structural changes (CT) in a single scan,

maximising the advantages of each type of scan.

Targeted radionuclide therapy employs a number of

different radiopharmaceuticals that can specifically

target cancer cells, resulting in a therapeutic radiation

dose to tumour tissue rather than normal tissues.

Whilst this technique has been successfully employed

for many years in a number of rare cancers including

thyroid and neuroendocrine tumours, novel agents

have now been developed for a wider range of

common tumours, including lymphoma.

Combined PET/CT imaging

The Royal Marsden installed one of the first PET/CT

scanners in the NHS in February 2004.

There is evidence that

the extra information

gained from combined

PET/CT imaging is

incremental and

complementary to

standard imaging in a

number of cancers

and positively affects

patients’ clinical

management in as

many as 30% of cases

compared to standard

techniques.

Work is currently underway at the Royal Marsden

PET/CT Unit in collaboration with Professor Janet

Husband (Head of the Department of Diagnostic

Radiology) and a number of clinical units to further

evaluate the role and efficacy of FDG-PET in a number

of clinical situations, in order that the use of this

valuable resource can be optimised to help tailor

treatment protocols in individual patients.

Recurrent colorectal cancer

In collaboration with Professor David Cunningham and

colleagues in the Gastrointestinal Unit, this project is

prospectively evaluating the contribution of FDG-PET

in clinical decision-making in patients in whom there

is suspicion of recurrent cancer as a result of a positive

tumour marker blood test (carcino-embryonic antigen

– CEA), but in whom standard imaging tests such as

CT are negative.


Lung cancer

In collaboration with Dr Mary O’Brien and colleagues in

the Royal Marsden’s Lung Unit, this project is evaluating

the contribution of FDG-PET/CT to the speed with

which therapy is instigated when used early on in the

investigation pathway. By using FDG-PET/CT at an early

stage soon after diagnosis it is possible that patients’

treatment pathways will be accelerated with a reduction

in delay to first treatment.

Figure 1 shows a combined FDG-PET/CT scan (PET

colour scale, CT grey scale) of a patient with lung cancer.

The tumour (colour) can easily be differentiated from

collapsed lung distal to the tumour (grey) that is not

involved by cancer. This type of information may be very

helpful in planning radiotherapy, with the potential to

delineate more accurately the boundaries of the tumour

compared to using CT alone.

Oesophageal cancer

Many patients with apparently operable oesophageal

cancer relapse after surgery because of small areas of

disease, which were undetectable by conventional

investigation at the time of surgery. FDG-PET is being

used to routinely stage patients with apparently operable

oesophageal cancer to measure its impact on subsequent

patient management (in collaboration with Mr William

Allum, Gastrointestinal Unit). It is possible that a number

of patients will be able to avoid futile surgery and receive

more appropriate treatment, eg chemotherapy. A further

project is planned in collaboration with Dr Diana Tait in

the Department of Radiotherapy to evaluate the role of

FDG-PET in planning radiotherapy in oesophageal cancer.

Lymphoma

In collaboration with Professor David Cunningham and

colleagues in the Lymphoma Unit, this project will

prospectively evaluate the role of FDG-PET/CT in clinical

decision making in patients who have received primary

chemotherapy but who are left with a residual tumour

mass in which it is not possible to differentiate residual

active tumour, which requires further treatment with

radiotherapy, from post-treatment scar tissue.

Further projects are underway or being planned to

evaluate the role of FDG-PET/CT in radiotherapy planning.

Areas of current interest include head and neck, lung and

oesophageal cancer as well as lymphoma.

collapsed lung

tumour

FDG-PET/CT in evaluating

response to treatment

Monitoring tumour metabolism has the potential to be

a more sensitive method in evaluating response to

anticancer treatments, because changes in tumour

metabolism often occur before a reduction in tumour

size is seen – a parameter currently used to assess

response with standard imaging methods. Many novel

anticancer drugs act by inhibiting specific aspects of

tumour metabolism rather than by the direct killing of

tumour cells as occurs with standard chemotherapy.

Successful treatment with these novel agents may

therefore be more easily appreciated using techniques

that measure tumour (a)

metabolism rather than

size reduction of the

tumour.

Figure 2 shows a

patient with a

gastrointestinal stromal

tumour in the liver and (b)

pelvis (Figure 2a). Two

months after starting

imatinib treatment, the

activity of the tumour

has completely resolved

(Figure 2b).

We are using FDG-PET/CT to measure treatment

response to at least three novel anticancer agents in

collaboration with colleagues in the Drug Development

Unit. Although the mechanism of action of these drugs

may differ, there is usually a common downstream effect

on tumour glucose transport and metabolism that can

be monitored by FDG-PET/CT.

Figure 1.

Combined FDG-PET/CT

scan (PET colour scale,

CT grey scale) of a

patient with lung

cancer. The tumour

(colour) can easily be

differentiated from

collapsed lung distal to

the tumour (grey) that

is not involved by

cancer.

Figure 2.

(a) Patient with a

gastrointestinal stromal

tumour in the liver

and pelvis.

(b) Two months after

starting imatinib

treatment, the tumour

has completely

resolved.

tumour

bladder

bladder

47


Figure 3.

Post-therapy SSR peptide

scan with physiological

hepatic, splenic and

bladder activity and

extensive metastases.

L - liver

S - spleen

B - bladder

Radioimmunotherapy

One of the most promising advances in radionuclide

treatment is radio-immunotherapy using isotopetumour

L

B

Targeted radionuclide therapy

Targeted therapy using therapeutic radioisotopes offers

several advantages compared with other cancer

treatments. Acting systemically, this approach allows

multiple tumour sites to be treated simultaneously with

relative sparing of healthy surrounding tissues. As a

result, toxicity is very low in comparison with other

systemic therapies and treatment is well tolerated.

Alternatives to the use of radioactive iodine

Radioactive iodine, for example, has been the mainstay

of post-surgical treatment for differentiated thyroid

cancer for over 50 years. In addition to therapeutic beta

particles, iodine also emits unwanted high-energy

gamma rays, which pose a significant radiation hazard

to staff and carers. Patients undergoing high-activity

treatment must therefore be nursed for several days

in dedicated, lead-lined isolation rooms. To overcome

these constraints, there is growing interest in the use

of alternative radioisotopes such as yttrium-90 ( 90 Y)

or alpha particle emitters, which might

allow treatment to be delivered safely

on an outpatient basis.

Designer radiopharmaceuticals

Recent advances have focused on

designer molecules, selected to recognise

and specifically target tumour cells. For

S

example, several bone-seeking

radiopharmaceuticals are now available

to treat metastatic skeletal pain.

Although effective for symptom

palliation, these treatments have not

been shown to prolong survival or to

have an anti-tumour effect. In a bid to

improve outcome, we are participating in

the first international, multicentre clinical

trial using an isotope of radium ( 223 Ra).

This is an alpha particle emitting

radioisotope predicted to deliver a

tumouricidal radiation dose to bone

metastases. The clinical programme is

supported by the development of new

methods for image quantification and

alpha particle dosimetry by the

Radioisotope Physics Team in the Joint Department

of Physics.

Radiolabelled peptides – their use for the

treatment of neuroendrocine tumours

The Royal Marsden has extensive experience using 131 I

meta iodobenzylguanidine ( 131 I mIBG) to treat refractory

neuroendocrine tumours and is participating in a

European study investigating the role of high activity

mIBG therapy with chemotherapy in childhood

neuroblastoma. However, only a minority of adult

neuroendocrine tumours concentrate mIBG sufficiently

well for this to be a realistic treatment option. By

contrast, over 90% of neuroendocrine tumours overexpress

surface receptors for a range of neuropeptides,

such as somatostatin. Targeted therapy using

radiolabelled peptides directed against somatostatin

surface receptors (SSR) offers a new treatment approach

for these tumours. Procedures were developed in 2004

by Royal Marsden radiochemists to label SSR analogues

with the isotope 90 Y. Over 100 patients have now been

referred for 90 Y peptide therapy from the UK and

abroad. An assessment programme has been

established to monitor clinical outcomes, including

quality of life assessment and will report later this year.

Targeted therapy using

radiolabelled peptides

directed against

somatostatin surface

receptors offers a new

treatment approach

for neuroendocrine

tumours.

Figure 3 shows a post-therapy SSR peptide scan with

physiological hepatic, splenic and bladder activity and

extensive metastases.


IMAGING RESEARCH & CANCER DIAGNOSIS

antibody conjugates directed against tumour cell surface

antigens. The CD20 antigen, for example, is a useful

target in B cell non-Hodgkin’s lymphoma (NHL). Building

on previous experience using the anti-CD20 monoclonal

antibody, rituximab, radio-labelled anti-CD20 antibodies

have now been licensed to treat relapsed NHL. Low

dose-rate radiation exploits the inherent radiosensitivity

of haematological malignancies and acts synergistically

with the biologically active antibody. Three patients with

refractory NHL have now been treated using 90 Y

labelled antibodies at the Royal Marsden.

The Radioisotope Physics Team is developing

methods for 90 Y quantification to enable prospective

individual treatment planning. This approach will be

critical to improving the efficacy of radioimmunotherapy

and has wider implications for targeted radionuclide

therapy in general.

Figure 4 shows a post-therapy anti-CD20 antibody

whole body scan with physiological liver and blood

pool activity and extensive left axillary, mesenteric and

iliac adenopathy.

The future

The unique availability of expertise in clinical PET,

radionuclide therapy, radiochemistry and dosimetry

physics at the Royal Marsden is encouraging research

investment and partnership with industry. Future

collaboration is planned that will bring together these

aspects of current research interest. Further work is

anticipated to develop targeted radionuclide dosimetry

techniques for novel therapies with radiopharmaceuticals,

using either PET/CT or single photon emission

computed tomography (SPECT)/CT to improve the

accuracy of these measurements.

The main areas of future research interest for PET/CT

are concerned with utilising alternative

radiopharmaceuticals to measure different aspects of

tumour metabolism.

A new cyclotron and radiochemistry facility is being

planned that will enable the production of novel

radiopharmaceuticals that will be used in future

research at the Royal Marsden and The Institute.

Examples include:

18 F-fluorothymidine to monitor increased DNA

synthesis in tumours and changes in activity as a

result of cytotoxic chemotherapy;

18 F-fluorocholine to measure abnormal cell

membrane metabolism in cancer, including

prostate cancer;

Radiopharmaceuticals designed to measure tumour

hypoxia (low oxygen levels), a factor that is known

to cause resistance to radiotherapy in a number of

cancers. Knowledge of the distribution of hypoxia

within a malignant tumour is likely to impact on the

way radiotherapy is planned and we are currently

collaborating in trials with Dr Chris Nutting and

colleagues in the Head and Neck Unit to determine

the impact of hypoxia imaging on intensity

modulated radiotherapy in head and neck cancers

with the goal of improving tumour control.

L

Figure 4.

Post-therapy anti-CD20

antibody whole body

scan with physiological

liver and blood pool

activity and extensive

left axillary, mesenteric

and iliac adenopathy.

L - liver

tumour

49


CANCER BIOLOGY/RADIOTHERAPY

Prostate Cancer:

new approaches are allowing a

better understanding of the disease

and its treatment

Ten years ago prostate cancer research at the Royal

Marsden and The Institute was in its infancy. Today there

are coordinated, linked research teams working across a

broad spectrum of areas. Our understanding of how the

disease develops and progresses is increasing, and we are

developing safe and more effective approaches to the

management of both localised and metastatic disease.

David Dearnaley

MA MD FRCR FRCP

Professor David Dearnaley

is a Team Leader in the

Section of Radiotherapy at

The Institute of Cancer

Research and Head of the

Urological and Testicular

Cancer Unit at The Royal

Marsden NHS Foundation

Trust

Amanda Swain

PhD

Dr Amanda Swain is a

Team Leader in Sexual

Development in the Section

of Gene Function and

Regulation at The Institute

of Cancer Research

Why is prostate cancer

different

Prostate cancer poses a unique set of challenges for the

laboratory scientist and clinician. As a result of prostate

specific antigen (PSA) testing, prostate cancer has now

become the most commonly diagnosed male cancer in the

western world with over 27,000 cases recorded annually

in the UK. It remains a major cause of mortality with

nearly 10,000 cancer deaths per year. Yet, paradoxically

most of the early prostate cancer now diagnosed by

PSA testing may not need treating at all. The rate of

progression is frequently so slow that the disease is of

no threat – indeed autopsy studies show microfocal

invasive disease in about 80% of 80-year-old men.

There is a pressing

need to understand

the processes that lead

to disease progression

in prostate cancer and

to determine the

effectiveness of local

curative treatments

and response to

hormonal therapy.

We also need to know much more about the

events leading to androgen independence, metastases

and death.

How does a normal

prostate develop

Some of the molecular pathways that are deregulated in

cancer cells are active during the development of the

organ during fetal and neonatal life, but are normally

switched off or are highly regulated in the adult.

Therefore, understanding how the prostate develops will

provide insight into the pathways that are important in

prostate cancer.

In the Section of Gene Function and Regulation, the

Sexual Development Team is studying the process of

early prostate development, which is induced by the

action of androgens, produced by the testis, on the

urogenital sinus. We have identified genes that are

specifically expressed in the newly formed prostatic

epithelial buds (Figure 1) and are studying the function

of these genes in this process. Through our links with

Professor Colin Cooper (Section of Molecular

Carcinogenesis) we are also investigating if these genes

can serve as clinical markers for different stages of

prostate cancer using tissue microarray (see below).

What are some of the causes

of prostate cancer

Cancer arises from a change in the balance between

cell self-renewal and differentiation. Many organs,

including the prostate, contain a small population of

cells, called stem cells, which have the unique ability to

differentiate into the different cell types that make up a

functional organ and are also capable of self-renewal.

Changes in the properties of these cells are thought to

drive the proliferation and survival of the cancer cell.

David Hudson (Section of Molecular Carcinogenesis)

is working to identify and characterise stem cells of the

human prostate to understand how proliferation and

differentiation are regulated in these cells. One goal of

this work is to identify stem cell specific markers and

investigate if they are aberrantly expressed in prostate

cancer and may provide suitable targets for

differentiation-based tumour therapy.


(a)

(b)

Figure 1.

Whole mount betagalactosidase

staining

marking the developing

prostatic buds in the

urogenital sinus.

(a) dorsal view;

(b) lateral view.

Pussycats and tigers

As many as 70% of the cancers diagnosed by PSA

testing and then trans-rectal ultrasound guided biopsy

may never lead to clinically important disease. This is

central to the dilemma about the value of PSA screening

for prostate cancer diagnosis. The standard clinical and

histological characteristics of these cancers are unable

to accurately predict outcome in the majority of cases.

Our research programmes are targeting this critical area

in several complementary ways. Molecular pathology

techniques have huge potential to exploit the mapping

of the human genome and unravel the complexity of

genetic modifications that underlie the development of

clinically significant cancer.

Tissue microarrays can be used to study and

evaluate the significance of large numbers of

immunocytochemical markers. Professor Colin

Cooper and his team have developed new

techniques to preserve tissue for DNA and RNA

analysis (Figure 2) at the time of radical

prostatectomy (ie when a prostate gland is

removed). This also allows for the production of

tissue microarrays, which in turn means that many

different types of investigations can be carried out

subsequently from the very small amount of starting

material now routinely taken during a prostate

biopsy. We have already shown that new gene

products E2F3 and HOX B13 are associated with a

poor clinical outcome. In the future, large numbers

of potential markers will be screened using our new

microarray technology.

These studies closely link with the active surveillance

research projects led by Chris Parker (Section of

Radiotherapy), which offer very detailed biochemical

(PSA), clinical and biopsy follow up rather than

immediate radical curative treatment for men with

good prognosis primary prostate cancer.

Approximately 100 men per year are being recruited

to the programme and initial results suggest that the

considerable majority of men may avoid the side

effects of radical treatment. The associated tissue

banks, consisting of serum, urine, peripheral blood

lymphocytes and prostate biopsy samples will

provide a unique resource for translational studies.

New markers will be tested and correlated with the

probability of cancer either remaining indolent and

harmless or of developing into progressive disease.

In parallel, imaging studies are exploring the role of

magnetic resonance imaging (MRI) and spectroscopy

(MRS) in identifying and characterising prostate

cancers. The intention here is to develop noninvasive

methods for predicting the aggressiveness

of disease (see Figure 2).

51


Figure 2.

A new system for slicing

and preparing radical

prostatectomy specimens

(patent pending). Tissue

can be taken and stored for

subsequent DNA and RNA

analysis whilst preserving

the tissue for histological

diagnosis and also

compared with novel MR

imaging methods. Prostate

slices are orientated in a

similar plane to MRI

images taken prior to

prostatectomy so that new

imaging techniques using

diffusion-weighted MRI,

dynamic contrast-enhanced

MRI or MRS can be

compared with

histopathological

assessment. MRI and MRS

characteristics are being

compared with tumour

aggressiveness and the

accuracy of tumour

localisation used to further

refine radiotherapy

techniques. This project

illustrates the very close

collaboration between the

Departments of Urological

Surgery, Histopathology,

Radiology and Magnetic

Resonance, Joint

Departments of Physics and

Radiotherapy as well as the

Male Urological Cancer

Research Centre.

(a) (b) (c)

(a) inked, fresh prostate in custom-made holder

(b) multibladed knife for use with holder

(c) resulting prostate slices

(d) dynamic MR parameter map

(e) corresponding whole-mount pathology section

(f) resulting receiver operating characteristic

(d) (e) (f)

Improving efficacy and

reducing side effects of

treatment for localised disease

Radical radiotherapy and prostatectomy are the

established curative options for localised disease. The

Radiotherapy Departments's programme of research with

the Joint Department of Physics has continued to develop

improved radiotherapy methods and to take these

forward into institutional and national clinical trials.

Improvement in PSA control rates

A pilot, randomised, radiation dose escalation study

(64 Gy vs 74 Gy), using conformal radiotherapy

techniques undertaken at the Royal Marsden/The

Institute has shown a 12% improvement in PSA control

rates at 5 years and a reduction in rectal and bladder

side effects using a small radiation safety margin, which

is now possible through the development of methods to

improve treatment accuracy. A national trial involving

850 men has now been completed.

shorten the overall treatment time from 7.5 to 4 weeks

for early localised disease. Recent radiobiological studies

suggest larger daily treatments may be a more effective

treatment strategy, which would be more convenient

for patients and make better use of resources. With

Department of Health funding we have now taken this

trial forward nationally with a comprehensive quality

assurance programme to allow more widespread

introduction of these advanced techniques.

Brachytherapy

Brachytherapy uses implantation of small radioactive

iodine seeds into the prostate. This has become a very

popular method of treatment in the USA with

encouraging long-term results. A recent donation to

Vincent Khoo (Department of Radiotherapy) from the

Master Masons has facilitated the development of a

new brachytherapy service at the Royal Marsden.

Men within the South West Thames Cancer Network

will now have full access to state of the art surveillance,

radiotherapy and surgical options.

Intensity modulated radiotherapy (IMRT)

Intensity modulated radiotherapy (IMRT) methods

shrink-wrap the radiation dose around the cancer,

thereby substantially avoiding normal tissues and

reducing side effects. IMRT techniques are currently

being studied for pelvic lymph node irradiation and to

Treatment of recurrent and

metastatic disease – new

approaches and targets

Advanced prostate cancer is characterised most

commonly by a pattern of sclerotic osteoblastic bone


CANCER BIOLOGY/RADIOTHERAPY

metastases and resistance to treatment with standard

hormonal therapy by androgen suppression. The

mechanism for this bone trophism (ie the prostate

cancer heading towards bone) and the hormone

refractory state are poorly understood. Recently

analysed studies have evaluated the roles of

bisphosphonate drugs, the anti-endothelin agent

atrasentan and high dose (activity) bone-seeking

isotope radiation treatment. Preliminary results suggest

benefit for all three approaches and the challenge now

is how to integrate these advances with chemotherapy

and other targeted treatment approaches.

A new Phase I drug development facility

Drug development for hormone refractory disease has

been significantly aided by the establishment of a new

Phase I drug development team led by Johann de Bono

(Section of Medicine) focusing on hormone refractory

prostate cancer. Agents targeting angiogenesis (VEGFR,

FGFR), epigenetics (demethylating agents and HDAC

inhibitors), cell signalling pathways (erbB, IGF-1R, mTOR)

and the androgen receptor (HDAC/HSP-90 inhibitors)

have been studied. Of particular importance, further trials

are now underway using abiraterone acetate (developed

by chemists at The Institute), which inhibits androgen

synthesis by blocking 17 alpha-hydroxylase.

Matched pairs of human prostate

cancer tissue

A critical issue as prostate cancer progresses from the

hormone sensitive to hormone resistant state is to

obtain matched pairs of human prostate cancer tissue

so as to identify the underlying molecular mechanisms

of disease progression and potential new targets for

treatment. A new programme has been successfully

funded and launched.

Surrogate end-points

Clinical studies that evaluate circulating tumour cells as

a surrogate endpoint in clinical trials have started and in

the future may be developed as an in vivo readout of the

effectiveness of novel agents on their specific targets.

DNA cancer vaccine

A new initiative established by the National

Cancer Research Institute South of England Prostate

Cancer Collaborative (sited in the Male Urological

Cancer Research Centre) is assessing the immunological

effects of a new DNA cancer vaccine directed against

the prostate specific membrane antigen with colleagues

at Southampton University, who have successfully

generated this novel plasmid vector. The first patient

has been treated within 3 years of the initial laboratory

development – an excellent example of the types of

achievement we can expect from the Prostate Cancer

Collaborative effort in the future.

The future – building

a foundation for

translational research

Our laboratory and clinical programmes will help

unravel the molecular mechanisms involved in the

progression of prostate cancer from a harmless

bystander into an aggressive metastatic malignancy

refractory to hormonal control. Tissue collections taken

in steps along this pathway may identify new targets

and suggest novel strategies designed to slow

progression of disease either using specifically designed

new molecules or dietary/environmental interactions.

Every man's prostate

cancer is different.

Our goal is to translate

the molecular

characterisation of

an individual's cancer

into strategies aimed

at containing or

eradicating the disease

in ways that will

produce maximal

benefit while reducing

treatment side effects

to a minimum.

53


HEALTH RESEARCH

Epidemiological

Studies

Genetic epidemiology: a tool for

finding the causes of cancer

In addition to investigating whether or not a certain

environment or behaviour causes a particular type of

cancer in people in general, we can now also investigate

if the effect of an exposure is different in specific types

of individual who differ in their genetic susceptibility

to cancer.

Anthony Swerdlow

PhD DM DSc FMedSci

Professor Anthony

Swerdlow is Chairman of

the Section of Epidemiology

at The Institute of Cancer

Research

Epidemiology and

risk factors

Epidemiologists seek to identify factors that alter the

risk of cancer in humans, so that if the factors are

causal they can be diminished, and if they are

preventative they can be increased. For example, by far

the largest change in cancer mortality in Britain during

the last century as a consequence of scientific research

was the decrease in lung cancer mortality that occurred

during the second half of the last century. This followed

from epidemiological studies that showed that the

major cause of lung cancer is tobacco smoking, and

that if smoking is stopped (or better if it is never

started) risk decreases greatly.

Frequency and mortality

The methods used 50 years ago to show the association

of tobacco smoking and lung cancer are the ones still in

use by the epidemiologists of today who seek to find

the causes of other cancers.

First, studies were conducted that compared the

frequency of smoking in lung cancer patients with

that in people who did not have lung cancer, and

it was found that the former smoked more than

the latter.

Secondly, comparisons were made between lung

cancer mortality in people who smoked and in those

who did not smoke. It was found that smokers died

more often from lung cancer than did non-smokers.

Because these observations were made in free-living

humans who differed in many other respects as well as

in their smoking habits, the conduct, design and

interpretation of the studies were not quite as

straightforward as the simplified description above

might suggest. Nevertheless, if such observations are

carefully carried out, are suitably analysed and are

judiciously interpreted, they provide a surprisingly potent

way of finding preventable causes of cancer. The use of

similar methods has shown, for example, that asbestos

inhalation is an important cause of respiratory cancers;

that working in the manufacture of certain dyestuffs

causes bladder cancer; and that exposure to ionising

radiation can cause a large range of malignancies.

Genetics and epidemiology

The recent burgeoning of the science of genetics has

added another weapon to the armoury for

epidemiological investigation. It is now becoming

possible not just to investigate whether a particular

environment or behaviour causes a particular type of

cancer in people in general, but also to find out the

effects of an exposure, perhaps very different, in specific

types of individual who differ in their genetic

susceptibility to cancer. This is important because cancer

is a disease of genetic damage, and it is likely that the

causes of each type of cancer are a mixture of genetic,

environmental and behavioural factors, which interact

with each other. Hence, the way in which the

environment and behaviours affect cancer risks may

differ according to a person’s genetic constitution.

Conversely, whether or not a person’s genetic

constitution leads them to develop cancer is likely to

depend on how they behave and on their environment.

Understanding these interactions brings the prospect

of a much more personalised and accurate picture of

individual cancer risks, and of the actions that might

be taken to diminish them.


It is likely that the

causes of each type

of cancer are a

mixture of genetic,

environmental and

behavioural factors,

which interact with

each other. Hence,

the way in which the

environment and

behaviours affect

cancer risks may differ

according to a person’s

genetic constitution.

Ultraviolet radiation, genetics and

skin cancer

An illustration from a genetic variable that can be

assessed easily by anyone in everyday life, without

needing genetic testing, shows the strong potential

of this approach to finding cancer causation.

The risk of skin cancer is greatly dependent on

the extent of exposure to an environmental factor, the

ultraviolet (UV) radiation in sunshine. The risk also

depends heavily, however, on an individual’s genotype

(ie their specific genetic makeup). People whose

genotype gives them a dark skin will be at much lower

risk of skin cancer, for the same amount of UV

exposure, than will those who have paler skins. The

process of natural selection did not make northern

Europeans well suited to live with tropical levels of UV

radiation. Thus, causation and prevention depend not

solely on environment, or behaviour, or genetics, but

on the combination of these. The risk of skin cancer is

relatively low for a person of dark skin genotype who

lives in the high UV tropics, as it is for a genetically high

55


molecular genetics. Two studies, one recently completed

and the other just started, give some picture of the

types of investigation in which we are now engaging

to address these issues.

risk Celtic redhead who lives in a temperate country.

The Celt who sunbathes on the beach in Queensland,

Australia, however, should not be so sanguine and the

use of targeted prevention measures, such as protective

sunscreens, is obvious.

Most genetic risk factors for cancers are not

outwardly perceptible, however, and therefore to

ascertain them requires genetic testing in the laboratory.

Such testing is now becoming practical on a large scale,

so that the opportunities for studies of epidemiology

and genetics in combination are opening up rapidly.

Studies of cancer causation

that combine epidemiology

and molecular genetics

The Institute’s Section of Epidemiology, in collaboration

with the Section of Cancer Genetics and with the

Breakthrough Toby Robins Breast Cancer Research

Centre, is setting up large-scale epidemiological studies

of cancer causation that combine epidemiology and

Causes of brain tumours

Brain tumours are a fairly common type of cancer, and

the most frequent of them, gliomas, are often rapidly

fatal. We know very little of their causation or how to

prevent them. The only known non-genetic cause is

exposure to ionising radiation (eg X-rays), which

accounts for very few cases. There is anxiety among

some members of the public, however, that radiofrequency

radiation from mobile phone use might be

a cause.

We are investigating the causes of brain tumours

using a study design called a case-control study. This

compares exposures, behaviours and genes between

patients who have brain tumours (cases) and people

who do not have this condition (controls). We have

collected data over the past 4 years from over 1,000

brain tumour patients, plus control patients, to search

for environmental and genetic causal factors. We are

now analysing the data that have been collected, both

within our own study and in combination with data

from other similar studies from other countries (in

order to gather even larger numbers).

Causes of breast cancer

The second example is a study approaching the problem

of cancer causation in a different way: starting with

people who have different levels of exposure to

potential causes and then following their subsequent

risks of breast cancer over time. This study, the

Breakthrough Generations study, is recruiting more

than 100,000 women to investigate, over time, whether

those who have greater levels of particular factors

(eg more exercise or greater radiation exposure) have

greater (or lower) risk of breast cancer than those with

less or none of these factors, and how this interacts

with their genetic predisposition. The study was publicly

launched in September 2004 and is progressing very

encouragingly. Over 10,000 women contacted us by

email or telephone in the first 24 hours after the launch

to express interest in joining.


HEALTH RESEARCH

The Breakthrough

Generations study

of the causes of breast

cancer is planned to

continue for 40 years

or more, producing

new results over that

period.The Section of

Epidemiology plans to

start further large-scale

studies of genetic

epidemiology of

various cancers over

the next few years.

The future

Studies that combine epidemiology with molecular

genetics offer enormous potential to find the causes

of cancer. Such studies, however, can take a very long

time. They are also large, and as a consequence they

are expensive.

Hence, one of the key differences between the

work of the Section of Epidemiology and that in many

other parts of The Institute is the time-frame in which

the studies are conducted. We are now analysing

studies that we have been conducting for more than

20 years, and we have other studies ongoing that

will continue for 40 years or longer.

In addition, the large number of subjects who

need to be included in such studies and the large

volume of data and blood samples that need to be

processed and stored, means that studies of this type

require considerable staffing, space and logistic support.

An appreciable part of The Institute’s new Genetic

Epidemiology Building will therefore be taken up with

handling and storage of materials from these studies.

We are greatly looking forward to moving into the new

facilities built to accommodate this expanding activity.

57


HEALTH RESEARCH

Dietary

Interventions

Lymphoedema, diet and body weight

in breast cancer patients

As the rates of success in the treatment of cancer improve,

the need to examine the side effects of treatment and the

quality of life of patients will increase. Dietary interventions

may represent an important approach to the management

of the unwanted effects of successful cancer treatment

Clare Shaw

PhD RD

Dr Clare Shaw is a

Consultant Dietitian in

Oncology at The Royal

Marsden NHS Foundation

Trust

Nutrition and dietetics

The Department of Nutrition and Dietetics is based in

the Rehabilitation Unit at the Royal Marsden. The

Department provides a service in the hospital that

routinely encompasses the following:

liaison with catering about the appropriate provision

of food service within the hospital;

providing advice to patients and carers relating to

food intake, specialised artificial nutrition and other

dietary issues such as nutritional supplements;

producing written information on diet and cancer

and attempting to base this advice on up-to-date

research evidence.

Areas of recent research work in the Department

have been to examine dietary interventions for

managing treatment side-effects in patients and to

compare the benefits of different energy supplements

in counteracting weight-loss in cancer patients.

Randomised controlled

studies to examine the

relationship between

lymphoedema, diet and

breast cancer

Lymphoedema, a swelling of the arm, is a potential

side-effect of surgical and radiotherapy treatment for

breast cancer. A small number of studies and reports,

dating back over the last 60 years, have made

reference to the potential effect of diet and body

weight on the aetiology and possible management of

lymphoedema. Specifically, references in the literature

do exist about the potentially beneficial influence of

weight reduction and low fat diets on arm swelling.

However, there have been no randomised controlled

trials to test this hypothesis.

Previously published research reports have

highlighted the possibility that dietary changes may

have a negative impact on a patient’s disease state

and its prognosis.

There have also been studies to assess the dietary

compliance of patients following a particular dietary

regimen. However, there have not been intervention

studies to examine the effectiveness of dietary

intervention in women with lymphoedema after

treatment for breast cancer. Randomised controlled

studies are needed to examine the relationship

between lymphoedema, diet and breast cancer.

Nutrition, lifestyle and the risk

of developing breast cancer

There are a number of established links between a

person’s nutrition lifestyle and the risk of developing

breast cancer. In postmenopausal women, obesity or

increased body weight has been associated with an

increased risk for the development of breast cancer.

Increased body weight in postmenopausal women

probably acts via an enhanced conversion of the steroid

hormone precursor androstendione to oestrogens in

adipose tissue. Women have a tendency to gain weight

if they are being treated for cancer, and higher body

weight has been shown in some studies to confer a

poorer disease prognosis. There also appears to be

a positive linear association between height and the


elative risk of developing breast cancer. This association

appears to be due to the growth promotional effects

of nutrition during early life, and the age of menarche

(ie the age at which menstruation commences).

Figure 1.

Assessing body

fat composition

using skinfold

thickness calipers

The causes of lymphoedema

The development of lymphoedema in women who have

undergone treatment for breast cancer depends on a

number of factors, including the extent of surgery and

radiotherapy to the axilla (ie the underarm area). There

are a number of published reports suggesting that obesity

predisposes to the development of lymphoedema. Some

proposed mechanisms to explain this have included:

fat necrosis with secondary infection, regional

axillary lymphangitis (ie infection of the lymph

channels) with sclerosis (ie a thickening of tissue due

to a pathological process) and vessel obstruction;

obesity causing enlargement of the upper arm

thereby reducing the support provided by the skin;

the muscle pump for advancing the lymph in the

lymphatics is less efficient within the flabby tissues;

delayed wound healing in obese patients.

Lymphoedema in

women who have

undergone treatment

for breast cancer has

been shown to have a

negative psychological

impact and contributes

to a lower quality of life.

How diet may help in the

management of lymphoedema

Diet may help in the management of lymphoedema

via the following mechanisms:

a reduction in the number of adipocytes (fat cells)

that would otherwise contribute to the swelling

of the affected limb;

a reduction in the size of adipocytes may have a

beneficial effect on the arm;

a reduction of fat under the arm (in the axilla)

may improve lymph drainage through this area.

Dietary intervention

and lymphoedema

The Department’s interest in the potential influence

of diet on the treatment of lymphoedema has

developed jointly with the Lymphoedema Service

in the Rehabilitation Unit at the Royal Marsden.

Previously published reports indicated that a low

fat diet might be of benefit to patients suffering from

lymphoedema of the arm. Here, the suggestion was

that low fat diets would encourage the mobilisation

of subcutaneous fat. However, it was not clear whether

this was independent of any general weight reduction

in the patients. A number of our own patients were

requesting dietary advice to lose weight, and in some

individuals there appeared to have been a certain

amount of benefit in terms of weight loss and the

management of the patients’ lymphoedema.

59


Figure 2.

Comparison of excess

arm volume before and

after the study period.

Each bar represents an

individual patient. Blue

bars = before dietary

intervention; red bars =

after dietary intervention.

Percentage excess arm volume

50

45

40

35

30

25

20

15

10

5

0

Weight reduction group

Control group

Therefore, we decided to investigate the possible

relationship between diet and lymphoedema in a more

systematic way to establish what benefit, if any, might

be achieved for patients with lymphoedema. Two

research studies were undertaken by the Department of

Nutrition and Dietetics in conjunction with the

Lymphoedema Service.

The first study showed that there was no

significant beneficial effect of a low fat diet in women

with lymphoedema, following treatment for breast

cancer, that were undergoing the usual procedure for

management of their lymphoedema. It appears

unlikely that a low fat diet alone has any effect

on the management of lymphoedema.

Interestingly, analysis

of the data has shown

a significant correlation

between weight loss

and a reduction in

lymphoedematous

arm volume.

Intervention study of weight

reduction in women with

lymphoedema following

treatment for breast cancer

A second intervention study focused on examining

whether weight reduction alone would influence the

management of lymphoedema following treatment for

breast cancer. The primary endpoint of the study was to

measure excess arm volume in the lymphoedematous

limb. Accordingly, limb volume measurements were taken

during the study (either manually, with a tape measure,

or using a perometer) and were compared with the same

limb at the beginning of the study. During the study we

focussed particularly on enhancing dietary compliance,

using a shorter intervention period, and also including

secondary endpoints that related to body image, selfesteem

and function.

It is important to note that for any dietary

intervention study to be effective there needs to be

compliance (ie patients need to stick to what they have

been asked to do) with the dietary regimen. Measuring

dietary compliance is often difficult, with a dietary diary

often being the main measure of food intake. Use of a

weighed food intake provides the most accurate data, but

this is difficult to carry out during the course of normal

daily life, and so may impinge on dietary intake. Other

methods are less accurate in their assessment of the size

of food portions, but are nevertheless easier to undertake.


HEALTH RESEARCH

Accordingly, in our randomised study, a photographic

representation of food portions was used to help

subjects record their intake. Food intake was assessed

by completion of three 7-day diaries, prior to, and

during, the 24-week study and by 24-hour recalls at

hospital visits. These dietary records were analysed for

nutritional content using a computer programme.

Calculated energy intakes were compared with

calculated multiples of basal metabolic rate, in order

to assess whether the records were a true reflection

of energy intake in normal circumstances. Patients

were randomly allocated to two dietary groups:

a control group receiving no dietary advice; a group

on a weight reduction diet. Both groups underwent the

usual limb compression treatment (hosiery or bandages)

for the management of their lymphoedema.

At the end of the 12-week intervention period, the

weight reduction group had a statistically significant

reduction in weight compared to the control group.

The weight reduction

group showed a

statistically significant

reduction in the

percentage of excess

arm volume during

the intervention period,

with the mean excess

arm volume changing

from 24% to 15%

when compared with

the control group

(Figure 2).

The future

As the success in treating cancer improves, the need

to examine the side effects of treatment and quality

of life issues for patients will increase. Although dietary

interventions may be beneficial for managing the

untoward consequences of treatment, we will need to

be sure that they are not detrimental in terms of

disease progression and long-term patient survival.

Research into the best

treatment options for

patients is obviously

essential. Increasingly,

however, other aspects

of patient care may

also have an important

role to play in the daily

lives of patients who

have successfully

completed treatment

and are now learning

to live with cancer.

61


INTERNET RESOURCES

Research Reports

on the Internet

Research areas on The Institute and the Royal Marsden

websites provide comprehensive reports of our research

programmes, details of newly awarded research grants,

and a searchable publications database.

The Institute and the Royal Marsden together form the

largest comprehensive cancer centre in Europe, and one

of the largest in the world. Our extensive research

programme ranges from basic laboratory research in

molecular cell biology, cancer genetics, radiation physics,

and drug development, through clinical trials involving

cancer patients, to healthcare research and

epidemiological studies in the human population.

The review articles in

this report describe

only a handful of our

research developments.

Further research

achievements and

research projects

currently underway can

be explored on The

Institute and the Royal

Marsden websites:

http://www.icr.ac.uk/research.html

http://www.royalmarsden.org/research

Our research resources on the Internet should keep

you up to date with our progress throughout the year.

Research projects

Our clinical and basic research programmes

extend across the causes, prevention, diagnosis and

treatment of cancer, and may be categorised into

seven broad themes:

Cancer biology

Cancer genetics

Cancer therapeutics

Molecular pathology

Radiotherapy

Imaging research and cancer diagnosis

Health research

A searchable database of almost 1,000 current and

recently completed projects is available online, at:

http://www.icr.ac.uk/projects

You can search the projects database by keyword,

researcher’s name, department, funding body and

research theme, and you may also browse a list of all

projects. Illustrated reports, describing the project’s

objectives and findings, are displayed for most of the

projects (see Figure 1).

Research publications

During 2004, Institute and Royal Marsden scientists

published over 380 primary research articles in peerreviewed

journals, such as the New England Journal

of Medicine, Nature and Cell, to name just a few.

Many of our world-class researchers were also

invited to contribute review articles to some of the

most prestigious journals in their fields. More than

80 review articles were published, including articles

in Nature Reviews: Molecular Cell Biology, Cancer

Cell and the Journal of Clinical Oncology.

A full listing of all our research publications

for 2004 and other years is available through the

online Research Publications Database, at:

http://miref.icr.ac.uk


In addition to browsing lists of research journals,

books or conferences, if you have a specific query you

can also search the database by researcher, department,

abbreviated journal title or keyword to retrieve

information quickly.

Figure 1.

A sample project

report in the

projects database.

Research grants and

industrial collaborations

Our research activities are funded from competitively

won peer-reviewed grants, government initiatives,

partnerships with industry and donations from the

public. In 2004, The Institute and the Royal Marsden

jointly devoted £83.2 million, received from all of these

sources, to support research and development and

academic activities.

During the year, 70 new research grants were

awarded. Details are available on The Institute’s

website, at:

http://www.icr.ac.uk/research/grants.html

In addition, we entered several new collaborations

with industrial partners and signed a number of related

licence agreements. For more information, see:

http://www.icr.ac.uk/research/industrial.html

63


RESEARCH DEPARTMENTS

Research

Departments

Our Research Centres, Departments,

Sections and Units

Our research is carried out across 34 centres, departments,

sections and units, many of which are joint divisions between

The Institute and the Royal Marsden. Our research is

categorised into seven broad research themes. The

departments associated with each of these themes are

shown below.

CANCER BIOLOGY

The Breakthrough Toby Robins Breast

Cancer Research Centre

DIRECTOR: Professor A Ashworth

Section of Cell and Molecular Biology and

Cancer Research UK Centre for Cell and

Molecular Biology

CHAIRMAN AND CENTRE DIRECTOR:

Professor C J Marshall

Section of Gene Function and Regulation

ACTING CHAIRMAN: Professor P W J Rigby

Section of Haemato-Oncology

CHAIRMAN: Professor M F Greaves

Section of Structural Biology

JOINT CHAIRMEN: Professor L H Pearl,

Professor D Barford

CANCER GENETICS

Section of Cancer Genetics

CHAIRMAN: Professor M R Stratton

Section of Paediatric Oncology, Cancer

Research UK Academic Unit of Paediatric

Oncology, and the Children's Cancer Unit

CHAIRMAN AND HEAD OF CLINICAL UNIT:

Professor A D J Pearson

CANCER THERAPEUTICS

Academic Department of Biochemistry

HEAD OF DEPARTMENT: Professor M Dowsett

Breast Unit

in association with the Section of Medicine

HEAD OF UNIT: Professor I E Smith

Cancer Research UK Centre for Cancer

Therapeutics, Section of Cancer Therapeutics

and Clinical Pharmacology Unit

CENTRE DIRECTOR AND SECTION CHAIRMAN:

Professor P Workman

Section of Clinical Trials

CHAIRMAN: Ms J M Bliss

Gastrointestinal Cancer Unit

in association with the Section of Medicine

HEAD OF UNIT: Professor D Cunningham

Gynaecology Unit

in association with the Section of Medicine

HEAD OF UNIT: Professor S B Kaye

Section of Haemato-Oncology

CHAIRMAN: Professor M F Greaves

Haemato-Oncology Unit

HEAD OF UNIT: Professor G Morgan

Lung Cancer Unit

in association with the Section of Medicine

HEAD OF UNIT: Dr M E R O’Brien

Section of Medicine, including the

Cancer Research UK Department of

Medical Oncology

CHAIRMAN AND HEAD OF DEPARTMENT:

Professor S B Kaye

Section of Paediatric Oncology, Cancer

Research UK Academic Unit of Paediatric

Oncology, and the Children's Cancer Unit

CHAIRMAN AND HEAD OF CLINICAL UNIT:

Professor A D J Pearson

Sarcoma Unit

in association with the Section of Medicine

HEAD OF UNIT: Professor I R Judson

Skin and Melanoma Unit

in association with the Section of Medicine

HEAD OF UNIT: Professor M E Gore


MOLECULAR PATHOLOGY

Section of Haemato-Oncology

CHAIRMAN: Professor M F Greaves

Section of Molecular Carcinogenesis

CHAIRMAN: Professor C S Cooper

Section of Paediatric Oncology, Cancer

Research UK Academic Unit of Paediatric

Oncology, and the Children's Cancer Unit

CHAIRMAN AND HEAD OF CLINICAL UNIT:

Professor A D J Pearson

IMAGING RESEARCH &

CANCER DIAGNOSIS

Anatomical Pathology Department

HEAD OF DEPARTMENT: Professor C Fisher

Academic and Service Departments of

Diagnostic Radiology

HEADS OF DEPARTMENTS: Professor J E S Husband

(Sutton), Dr D M King (Chelsea)

Cancer Research UK Clinical Magnetic

Resonance Research Group

JOINT DIRECTORS: Professor J E S Husband,

Professor M O Leach

Department of Nuclear Medicine

CONSULTANT: Dr G J R Cook

Joint Department of Physics

HEAD OF DEPARTMENT: Professor S Webb

RADIOTHERAPY

Head and Neck Cancer Unit

HEAD OF UNIT: Professor C M Nutting

Neuro-Oncological Cancer Unit

HEAD OF UNIT: Dr F Saran

Joint Department of Physics

HEAD OF DEPARTMENT: Professor S Webb

Section of Academic Radiotherapy and

Department of Radiotherapy

SECTION CHAIRMAN: Professor A Horwich

DEPARTMENT HEAD: Dr P R Blake

Thyroid and Isotope Treatment Unit

HEAD OF UNIT: Dr C L Harmer

Urology and Testicular Cancer Unit

HEAD OF UNIT: Professor D P Dearnaley

HEALTH RESEARCH

Section of Epidemiology, including the

Department of Health Cancer Screening

Evaluation Unit

CHAIRMAN: Professor A J Swerdlow

Cancer Research UK Epidemiology and

Genetics Unit

CHAIRMAN: Professor J Peto

Directorate of Nursing, Rehabilitation and

Quality Assurance

CHIEF NURSE AND DIRECTOR:

Dr D Weir-Hughes

Department of Pain and Palliative Medicine

HEAD OF SERVICES: Dr J Riley

Psychological and Pastoral Care and

Psychology Research Group

HEAD OF SERVICES: Dr M Watson

List reflects the status as at April 2005.

65


SENIOR STAFF & COMMITTEES 2004

Senior Staff & Committees 2004

THE INSTITUTE OF CANCER RESEARCH

BOARD OF TRUSTEES

Lord Faringdon (Chairman)

Dr J M Ashworth MA PhD DSc (Deputy Chairman)

Mr E A C Cottrell (Honorary Treasurer)

Professor P W J Rigby PhD FMedSci (Chief Executive)

Professor R J Ott PhD FInstP CPhys (Academic Dean)

Dr R Agarwal (from September 2004)

Sir Henry Boyd-Carpenter KCVO MA

Dr S E Foden MA DPhil

Mrs T M Green MA

Mr C Gutierrez (to September 2004)

Mr R A Hambro

Professor M O Leach PhD FInstP FIPEM CPhys

FMedSci

Professor A Markham DSc FRCP FRCPath FMedSci

Dr T A Hince MSc PhD (Alternate Director)

(to September 2004)

Dr M J Morgan PhD

Professor H R Morris FRS (to March 2004)

Miss C A Palmer MSc MHSM DipHSM

Dr D Weir-Hughes OStJ MA EdD RN FRSH

(Alternate Director)

Professor D H Phillips PhD DSc FRCPath

Miss A C Pillman OBE

Mr R E Spurgeon

Professor M Waterfield FRS FMedSci

Miss M I Watson MA MBA FCIPD

Dr D E V Wilman PhD CChem MRSC ARPS

(to October 2004)

Mr J M Kipling FCA (Secretary of The Institute

and Head of Corporate Services)

Professor A Horwich PhD FRCP FRCR FMedSci

(Director of Clinical Research and Development and

Head of the Clinical Laboratories)

Professor C J Marshall DPhil FRS FMedSci

(Chairman of the Joint Research Committee)

Professor K R Willison PhD

(Head of the Chester Beatty and Haddow Laboratories)

CORPORATE

MANAGEMENT GROUP

Professor P W J Rigby PhD FMedSci

(Chief Executive – Chairman)

Mr J M Kipling FCA (Secretary of The Institute and

Head of Corporate Services)

Professor A Horwich PhD FRCP FRCR FMedSci

(Director of Clinical Research and Development and

Head of the Clinical Laboratories)

Professor S B Kaye MD FRCP FRCR FRSE FMedSci

Professor R J Ott PhD FInstP CPhys (Academic Dean)

Professor K R Willison PhD (Head of the Chester

Beatty and Haddow Laboratories)

Professor P Workman PhD FIBiol FMedSci

SECTION CHAIRMEN

Chester Beatty Laboratories

Professor A Ashworth PhD FMedSci (Director, The

Breakthrough Toby Robins Breast Cancer Research Centre)

Professor D Barford DPhil FMedSci (Section of

Structural Biology) (from November 2004)

Professor P W J Rigby PhD FMedSci (Acting Chair

of the Section of Gene Function and Regulation)

Professor M F Greaves PhD FRCPath FRS FMedSci

(Section of Haemato-Oncology)

Professor C J Marshall DPhil FRS FMedSci

(Section of Cell and Molecular Biology and Director, Cancer

Research UK Centre for Cell and Molecular Biology)

Professor L H Pearl PhD (Section of Structural Biology)

(to November 2004)

Clinical Laboratories

Ms J M Bliss MSc FRSS (Section of Clinical Trials)

(from January 2004)

Professor M Dowsett PhD (Academic Department

of Biochemistry)

Professor A Horwich PhD FRCP FRCR FMedSci

(Section of Radiotherapy)

Professor J E S Husband OBE FRCP FRCR FMedSci

(Co-Director, Cancer Research UK Clinical Magnetic

Resonance Research Group)

Professor S B Kaye MD FRCP FRCR FRSE FMedSci

(Section of Medicine and Cancer Research UK Medical

Oncology Unit)

Professor M O Leach PhD FInstP FIPEM CPhys

FMedSci (Co-Director, Cancer Research UK Clinical

Magnetic Resonance Research Group)

Professor K Pritchard-Jones PhD FRCPCH FRCPE

(Acting Chair of Section of Paediatric Oncology)

Professor S Webb PhD DIC DSc ARCS FInstP FIPEM

FRSA CPhys (Joint Department of Physics)

Haddow Laboratories

Professor C S Cooper DSc FMedSci

(Section of Molecular Carcinogenesis)

Professor M R Stratton PhD MRCPath FMedSci

(Section of Cancer Genetics)

Professor A J Swerdlow PhD DM DSc FFPH FMedSci

(Section of Epidemiology)

Professor P Workman PhD FIBiol FMedSci

(Section of Cancer Therapeutics and Director,

Cancer Research UK Centre for Cancer Therapeutics)

JOINT RESEARCH COMMITTEE

The Institute and the Royal Marsden

Professor C J Marshall DPhil FRS FMedSci (Chairman)

Professor A Ashworth PhD FMedSci

Professor M E Gore PhD FRCP (to July 2004)

Professor M F Greaves PhD FRCPath FRS FMedSci

Professor A Horwich PhD FRCP FRCR FMedSci

Dr R S Houlston MD PhD FRCP FRCPath

Professor J E S Husband OBE FRCP FRCR FMedSci

(to July 2004)

Dr S R D Johnston MA PhD FRCP

(from September 2004)

Professor S B Kaye MD FRCP FRCR FRSE FMedSci

Dr C Nutting MD MRCP FRCR (from September 2004)

Miss C A Palmer MSc MHSM DipHSM

Professor P W J Rigby PhD FMedSci

Professor I E Smith MD FRCP FRCPE (to July 2004)

Professor M R Stratton PhD MRCPath FMedSci

Professor K R Willison PhD

Professor P Workman PhD FIBiol FMedSci


ACADEMIC BOARD

The Institute and the Royal Marsden

Professor R J Ott PhD FInstP CPhys

(Chairman and Academic Dean)

Professor P W J Rigby PhD FMedSci (Chief Executive)

Professor A L Jackman PhD

(Deputy Dean, Biomedical Sciences)

Professor K Pritchard-Jones PhD FRCPCH FRCPE

(Deputy Dean, Clinical Sciences)

Dr G W Aherne* PhD

Dr K Allen PhD

Professor A Ashworth PhD FMedSci

Dr J C Bamber PhD

Professor D Barford DPhil FMedSci

Mr D P J Barton MRCOG FRCS

Ms J M Bliss* MSc FRSS

Professor M Brada FRCP FRCR

Dr G J R Cook MD FRCP FRCR

Professor C S Cooper DSc FMedSci

Professor D Cunningham MD FRCP

Professor D P Dearnaley MA MD FRCP FRCR

Dr N de Souza* MD FRCP FRCR

Professor M Dowsett PhD

Dr S A Eccles* PhD

Dr R Eeles* PhD FRCP FRCR

Dr P M Evans* DPhil MInstP MIMA

Dr B Felicetti PhD

Professor C Fisher MD DSc(Med) FRCPath

Dr G Flux PhD

Dr G H Goodwin* PhD

Professor M E Gore PhD FRCP

Professor M F Greaves PhD FRCPath FRS FMedSci

Ms S Hockley

Professor A Horwich PhD FRCP FRCR FMedSci

Dr R S Houlston* MD PhD FRCP FRCPath

Dr R A Huddart PhD MRCP FRCR

Dr D Hudson PhD

Professor J E S Husband OBE FRCP FRCR FMedSci

Professor C Isacke DPhil

Professor I R Judson MD FRCP

Dr M Katan* PhD

Professor S B Kaye MD FRCP FRCR FRSE FMedSci

Professor M O Leach PhD FInstP FIPEM CPhys

FMedSci

Dr W Liu PhD CBiol MIBiol

Dr R Marais* PhD

Professor C J Marshall DPhil FRS FMedSci

Dr E Matutes* MD PhD FRCPath

Dr S Mittnacht* PhD

Professor G J Morgan PhD FRCP FRCPath

Professor P S Mortimer MD FRCP MRCS

Dr S M Moss* PhD HonMFPH

Dr G Payne DPhil MInstP MIPEM

Professor L H Pearl PhD

Professor J Peto DSc HonMFPH FIA FMedSci

Professor D H Phillips PhD DSc FRCPath

Dr S Popat PhD MRCP

Mrs J Provin MA PGCEA

Professor N Rahman PhD MRCP

Mr P H Rhys-Evans DCC LRCP FRCS

Dr J M Shipley* PhD

Mr H Smith

Professor I E Smith MD FRCP FRCPE

Dr K Snell* PhD FRSA LRPS

Professor C J Springer PhD CChem FRSC

Professor M R Stratton PhD MRCPath FMedSci

Professor A J Swerdlow PhD DM DSc FFPH FMedSci

Dr G R ter Haar* DSc PhD FIPEM FAIUM

Dr M Watson PhD DipClinPsychol AFBPS

Professor S Webb PhD DIC DSc ARCS FInstP FIPEM

FRSA CPhys

Dr K M Weston PhD

Professor K R Willison PhD

Professor P Workman PhD FIBiol FMedSci

Mr A C Wotherspoon MRCPath

Professor J R Yarnold MRCP FRCR

Dr A Z Zelent* MPhil PhD

*Reader

FACULTY AND

HONORARY FACULTY

The Institute and the Royal Marsden

Dr G W Aherne* PhD

Dr M Ashcroft* PhD

Professor A Ashworth* PhD FMedSci

Dr J C Bamber* PhD

Professor D Barford* DPhil FMedSci

Ms J M Bliss* MSc FRSS

Dr J de Bono PhD FRCP

Dr J Boyes* PhD (to November 2004)

Professor M Brada* FRCP FRCR

Dr L Bruno PhD

Dr I Collins* PhD

Professor C S Cooper* DSc FMedSci

Professor D Cunningham* MD FRCP

Dr D R Dance* PhD FInstP FIPEM CPhys

Professor D P Dearnaley* MA MD FRCP FRCR

Professor M Dowsett* PhD

Dr S A Eccles* PhD

Dr R A Eeles* PhD FRCP FRCR

Dr T G Q Eisen PhD FRCP

Dr P M Evans* DPhil FInstP MIMA

Professor C Fisher* MD DSc(Med) FRCPath

Dr M A Flower* PhD (to September 2004)

Dr G Flux* PhD (from January 2004)

Dr M D Garrett* PhD

Dr G H Goodwin* PhD

Professor M E Gore* PhD FRCP

Professor M F Greaves* PhD FRCPath FRS FMedSci

Dr E Hall PhD

Dr K J Harrington MRCP FRCR

Professor A Horwich* PhD FRCP FRCR FMedSci

Dr R S Houlston* MD PhD FRCP FRCPath

Dr R A Huddart* PhD MRCP FRCR

Professor J E S Husband* OBE FRCP FRCR FMedSci

Professor C Isacke* DPhil

Professor A L Jackman* PhD

Dr S R D Johnston MA PhD FRCP

(from September 2004)

Dr C Jones PhD

Dr C M Jones* PhD (to August 2004)

67


Professor I R Judson* MD FRCP

Dr M Katan* PhD

Professor S B Kaye* MD FRCP FRCR FRSE FMedSci

Professor S R Lakhani* MD FRCPath

(to September 2004)

Dr R Lamb PhD

Professor M O Leach* PhD FInstP FIPEM

CPhys FMedSci

Dr S Linardopoulos PhD

Dr E McDonald* MA PhD ARCS

Dr R M Marais* PhD

Professor C J Marshall* DPhil FRS FMedSci

Dr E Matutes* MD PhD FRCPath

Dr P Meier PhD

Dr J Melia* PhD HonMFPH

Dr S Mittnacht* PhD

Professor G J Morgan* PhD FRCP FRCPath

(from January 2004)

Dr S M Moss* PhD HonMFPH

Professor R J Ott* PhD FInstP CPhys

Professor L H Pearl* PhD

Professor J Peto* DSc HonMFPH FIA FMedSci

Professor D H Phillips* PhD DSc FRCPath

Dr C Porter* PhD

Professor K Pritchard-Jones* PhD FRCPCH FRCPE

Professor N Rahman* PhD MRCP

Professor P W J Rigby* PhD FMedSci

Dr J M Shipley* PhD

Professor I E Smith* MD FRCP FRCPE

Dr K Snell* PhD FRSA LRPS

Dr C W So* PhD (from October 2004)

Dr N de Souza* MD FRCR FRCP (from February 2004)

Professor C J Springer* PhD CChem FRSC

Professor M R Stratton* PhD MRCPath FMedSci

Dr A Swain* PhD

Professor A J Swerdlow* PhD DM DSc FFPH FMedSci

Dr G R ter Haar* DSc PhD FIPEM FAIUM

Professor S Webb* PhD DIC DSc ARCS FInstP FIPEM

FRSA CPhys

Dr K M Weston* PhD

Professor K R Willison* PhD

Professor P Workman* PhD FIBiol FMedSci

Professor J R Yarnold* MRCP FRCR

Dr A Z Zelent* MPhil PhD

*Staff with University of London Teacher Status

Other Staff who are Teachers

of the University of London

Dr P R Blake MD FRCR

Dr V Brito-Babapulle PhD FRCPath

Dr G Brown PhD

Dr G J R Cook MD FRCP FRCR

Dr J Filshie FFARCS

Mr G P H Gui MS FRCS FRCSE

Dr A Hall PhD

Dr C L Harmer FRCP FRCR

Dr D L Hudson PhD

Dr A D L MacVicar MRCP FRCR

Professor P S Mortimer MD FRCP MRCS

Dr E C Moskovic MRCP FRCR

Dr C Nutting MD MRCP FRCR

Dr M E R O’Brien MD FRCP

Dr G Payne DPhil MInstP MIPEM

Dr F I Raynaud PhD

Mr P H Rhys-Evans DCC LRCP FRCS

Dr G M Ross PhD MRCP FRCR

Dr M F Scully PhD

Dr P Serafinowski PhD FRSC

Dr D M Tait MD MRCP FRCR

Dr J G Treleaven MD MRCP MRCPath

Dr M I Walton PhD

Dr M Watson PhD DipClinPsychol AFBPS

CORPORATE SERVICES

DIRECTORS

Mr J M Kipling FCA (Secretary of The Institute and

Head of Corporate Services)

Mrs E Bennett (Assistant Company Secretary)

Mr P J Black (Director of Fundraising)

Dr S Bright PhD (Director of Enterprise)

Mr A G Brown HonCIPFA (Senior Internal Auditor)

Mr J M Harrington BA MSc (Director of IT)

Mrs J Provin MA PGCEA

(Director of Corporate Development)

Mrs C Scivier MSc FCIPD (Director of Human Resources)

Dr K Snell PhD FRSA LRPS

(Scientific Secretary and Director of Research Services)

Mr S Surridge BSc MRICS MBIFM MCMI

(Director of Facilities & Assistant Secretary)

Mr A Whitehead ACA (Director of Finance)

THE ROYAL MARSDEN NHS FOUNDATION TRUST

BOARD OF DIRECTORS

Non-Executive

Mrs T Green MA (Chairman)

Ms F Bates (Vice Chairman)

Mr J Burke QC

Mr M Khosla

Mr S Purvis CBE

Professor P W J Rigby PhD FMedSci

Executive

Miss C A Palmer MSc MHSM DipHSM

(Chief Executive)

Mr A Goldsman MSc ACA (NZ)

(Director of Finance and Information)

Professor J E S Husband OBE FRCP FRCR FMedSci

(Medical Director)

Dr D Weir-Hughes OStJ MA EdD RN FRSH

(Chief Nurse/Deputy Chief Executive)

Other Directors

Mrs N Browne (Director of Strategy and Service

Development) (from June 2004)

Mrs N French MA MIPD

(Director of Human Resources)

Professor A Horwich PhD FRCP FRCR FMedSci

(Director of Clinical Research and Development)

Dr J Milan PhD (Director of Information)

Mr R D Thomas BSc DMS CEng MICE MInstD

(Director of Facilities)


SENIOR STAFF & COMMITTEES 2004

MEDICAL ADVISORY

COMMITTEE

Professor J E S Husband OBE FRCP FRCR FMedSci

(Medical Director – Chairman)

Dr P R Blake MD FRCR (Head of Radiotherapy Services)

Professor D Cunningham MD FRCP

(Head of Gastrointestinal and Lymphoma Units)

Professor D P Dearnaley MA MD FRCP FRCR

(Head of Urology Unit)

Professor M Dowsett PhD (Head of Academic

Department of Biochemistry) (to July 2004)

Dr R Eeles PhD FRCP FRCR (Team Leader,

Cancer Genetics) (from January 2004)

Professor C Fisher MD DSc(Med) FRCPath

(Head of Anatomical Pathology Department)

Mrs N French MA MIPD (Director of Human Resources)

(to September 2004)

Mr A Goldsman MSc ACA(NZ) (Director of Finance

and Information)

Professor M E Gore PhD FRCP

(Divisional Director, Rare Cancers)

Dr C L Harmer FRCP FRCR (Head of Thyroid Unit)

Professor A Horwich PhD FRCP FRCR FMedSci

(Academic Radiotherapy Unit and Director of Clinical

Research and Development)

Dr R Huddart PhD MRCP FRCR

Dr C Irving FRCA (Lead Anaesthetist)

Professor I R Judson MD FRCP

(Head of Sarcoma Unit)

Dr S R D Johnston MA PhD FRCP

(Consultant: Breast & Gynaecology Units)

Professor S B Kaye MD FRCP FRCR FRSE FMedSci

(Chairman, Drug and Therapeutics Advisory Committee)

Dr D M King DMRD FRCR (Consultant Radiologist)

Professor G J Morgan PhD FRCP FRCPath

(Head of Haemato-Oncology Unit) (from January 2004)

Dr C Nutting MD MRCP FRCR

(Head of Head and Neck Unit)

Dr M E R O’Brien MD FRCP (Head of Lung Unit)

Miss C A Palmer MSc MHSM DipHSM (Chief Executive)

Professor K Pritchard-Jones PhD FRCPCH

(Acting Head of Paediatric Unit)

Dr G M Ross PhD MRCP FRCR

(Deputy Head of Breast Unit) (to April 2004)

Dr F Saran MD MRCR (Consultant Neuro-oncologist)

Mr N P M Sacks MS FRACS FRCS

(Lead Surgeon, Theatres)

Mr J Shepherd (Consultant Gynaecologist, Surgeon)

Professor I E Smith MD FRCP FRCPE

(Consultant: General Medicine, Head of Breast Unit)

Dr D M Tait MD MRCP FRCR (Head of Clinical Audit)

Mr N Watson MSc MRPharmS MBA (Chief Pharmacist)

Dr D Weir-Hughes OStJ MA EdD RN FRSH

(Chief Nurse/Director of Nursing, Rehabilitation and

Quality Assurance)

COMMITTEE FOR

CLINICAL RESEARCH

The Institute and the Royal Marsden

Mr R P A'Hern MSc

Dr M J Allen MRCP (from December 2004)

Dr K Broadley MRCP (to August 2004)

Ms F Davies MSc RN (from September 2004)

Professor M Dowsett PhD (Deputy Chair)

Dr T G Q Eisen PhD FRCP

Ms C Fry MSc (to July 2004)

Ms H Hollis RN RNT PGDip MSc

Mr G P H Gui MS FRCS FRSCE

Dr K J Harrington MRCP FRCR

Dr R S Houlston MD PhD FRCP FRCPath

(to August 2004)

Dr R A Huddart PhD MRCP FRCR

Dr S R D Johnston MA PhD FRCP (Chair)

Dr D Lawrence MA MPhil PhD

Ms J Lawrence BSc (from October 2004)

Dr I Locke MRCP

Dr E Matutes MD PhD FRCPath

Dr M E R O'Brien MD FRCP

Dr F I Raynaud PhD

Dr S Rogers MRCP FRCR

Dr S A A Sohaib MRCP FRCR

Mr A C Thompson FRCS

Mrs C Viner SRN Onc FETC MSc

Dr J Waters PhD MRCP (to July 2004)

CLINICAL RESEARCH

DIRECTORATE

The Institute and the Royal Marsden

Professor A Horwich PhD FRCP FRCR FMedSci

(Chairman and Director of Clinical Research and

Development)

Professor A Ashworth PhD FMedSci

Professor C S Cooper DSc FMedSci

Professor J E S Husband OBE FRCP FRCR FMedSci

Professor S B Kaye MD FRCP FRCR FRSE FMedSci

Miss C A Palmer MSc MHSM DipHSM

Professor P W J Rigby PhD FMedSci

Dr K Snell PhD FRSA LRPS (Joint Scientific Secretary)

CONSULTANTS AND

HONORARY CONSULTANTS

Anaesthetics

Dr G P R Browne DA FFARCS

Dr D Chisholm MRCP FRCA

Dr W P Farquar-Smith PhD FRCA

Dr J Filshie FFARCS

Dr M Hacking FRCA

Dr C J Irving FRCA

Dr J J Kothari FFARCS

Dr A Oliver FRCA

Dr J E Williams FRCA

Dr C Carr DA FRCA DICM

Dr D Burton FRCA (Locum) (from February 2004)

Dr P Suaris FRCA (Locum) (from August 2004)

Dr J Mitic MD DEAA FFARCSI (Locum)

(from December 2004)

Cancer Genetics

Dr R A Eeles PhD FRCP FRCR

Dr R S Houlston MD PhD FRCP FRCPath

Dr N Rahman PhD MRCP

Professor M R Stratton PhD MRCPath FMedSci

Drug Development

Professor I R Judson MD FRCP

Dermatology

Dr C Bunker MD FRCP

Professor P S Mortimer MD FRCP MRCS

69


SENIOR STAFF & COMMITTEES 2004

Epidemiology

Professor A J Swerdlow

PhD DM DSc FFPH FMedSci

General Surgery

Mr W H Allum MD FRCS

Mr M A Clarke MD FRACS (Locum) (to May 04)

Mr S R Ebbs MS FRCS

Mr G P H Gui MD FRCS FRCSEd

Mr A J Hayes MA FRCS PhD (from April 04)

Mr M M Henry FRCS

Mr J Meirion Thomas MS MRCP FRCS

Mr G Querci-della-Rovere MD FRCS

Mr N P M Sacks MS FRACS FRCS

Mr J N Thompson MA FRCS

Gynaecology

Mr D P J Barton MD MRCOG FRCSEd

Ms J E Bridges MRCOG

Mr T Ind MD MRCOG RCOG CCST

Mr I J Jacobs MD MRCOG

Mr C Perry MD FRCOG

Mr J H Shepherd FRCOG FRCS FACOG

Haematology

Dr C E Dearden MD MRCP MRCPath

Dr M E Ethell MA MRCP MRCPath (from July 2004)

Professor G J Morgan PhD FRCP FRCPath

(from January 2004)

Dr E Matutes MD PhD FRCPath

Dr M N Potter MA PhD FRCP FRCPath

(from May 2004)

Dr J G Treleaven MD MRCP MRCPath

Histopathology and Cytopathology

Dr N Al-Nasiri FRCPath

Professor C Fisher MD DSc(Med) FRCPath

Professor S R Lakhani MD FRCPath

(to September 2004)

Dr A Y Nerurkar MD DNB

Dr P Osin MD MRCPath

Dr A C Wotherspoon MRCPath

Medical Microbiology

Dr U Riley MRCP MRCPath

Medical Oncology

Professor D Cunningham MD FRCP

Dr J De Bono PhD FRCP

Dr T G Q Eisen PhD FRCP

Professor M E Gore PhD FRCP

Dr S R D Johnston MA PhD FRCP

Professor S B Kaye MD FRCP FRCR FRSE FMedSci

Dr M E R O’Brien MD FRCP

Dr B M Seddon PhD MRCP FRCR

Professor I E Smith MD FRCP FRCPE

Dr G Chong (Locum) MD FRCP

(from July 2004)

Nuclear Medicine

Dr G J R Cook MD FRCP FRCR

Professor R Underwood MD FRCP FRCR FESC

Dr V Lewington MSc FRCP

(from January 2004)

Occupational Health

Dr B J Graneek MRCP AFOM

Ophthalmology

Mr R A F Whitelocke PhD FRCS FRCOphth

Oral Surgery

Mr D J Archer FDSRCS FRCS

Otolaryngology

Mr P M Clarke FRCS

(from October 2004)

Mr P H Rhys-Evans DCC LRCP FRCS

Paediatrics

Dr A Albanese MD MPhil MRCP

Dr D R Hargrave MRCPCH

Dr D L Lancaster MD MRCP(UK) MRCPH

Professor K Pritchard-Jones PhD FRCPCH FRCPE

Dr M M Taj FMGEMDCH MRCP

Palliative Medicine

Dr K Broadley MRCP (to December 2004)

Dr A Davies MD MRCP (from June 2004)

Dr J Riley MRCGP

Psychological Medicine

Dr M Watson PhD DipClinPsychol AFBPS

Radiology

Dr G Brown MRCP FRCR

Professor J E S Husband OBE FRCP FRCR FMedSci

Dr P Kessar MRCP FRCR

Dr D M King DMRD FRCR

Dr M Koh MRCP FRCR

Dr A D L MacVicar MRCP FRCR

Dr E C Moskovic MRCP FRCR

Dr B Sharma FRCR BMMRCP

Dr S A A Sohaib MRCP FRCR

Dr R Pope MRCP FRCR

Radiotherapy

Dr P R Blake MD FRCR

Professor M Brada FRCP FRCR

Professor D P Dearnaley MA MD FRCP FRCR

Dr J P Glees MD FRCR DMRT

Dr K J Harrington MRCP FRCR

Dr C L Harmer FRCP FRCR

Professor A Horwich PhD FRCP FRCR FMedSci

Dr R A Huddart PhD MRCP FRCR

Dr V S B Khoo MD FRACR

Dr C Nutting PhD FRCP

Dr G M Ross PhD MRCP FRCR

Dr A Y Rostom DMRT FRCR

Dr F Saran MD MRCR

Dr D M Tait MD MRCP FRCR

Professor J R Yarnold MRCP FRCR

Reconstructive Surgery

Mr A Searle FRCS FRCS(Plast)

Mr P A Harris MD FRCS(Plast) (from May 2004)

Urological Surgery

Mr T Christmas MD FRCS

Mr A C Thompson FRCS

Mr C R J Woodhouse FRCS FEBU

More magazines by this user
Similar magazines