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