Joint Annual Research Report 2004 - The Royal Marsden

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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
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