The difference we made in 2006-07
Clinical Research
Scientific Research
Summary
Introduction
Having been recognised by the director of the Institute of Cancer in the Bart’s & London School of Medicine as pivotal in establishing the Experimental Cancer Medicine Centre in the latter part of 2005/06, the research programmes funded by Orchid have continued to produce important results in their own right. The Orchid genito-urinary clinical trials unit, working closely with the molecular therapeutic and carcinogenesis teams, and drawing on the invaluable work of the Orchid Tissue Bank, exemplify the combination of scientific and medical investigative work, commonly known as translational research. This holistic ‘bench-top to bed-side’ approach, for so long championed by Professor Tim Oliver, is the Government’s number one priority for research, focusing as it does on converting advances in the laboratory into better patients outcomes. A full description of the progress of the work is available on application to the Orchid head office. The following is a summary:
CLINICAL RESEARCH (Dr Jonathan Shamash (programme leader); Dr Tom Powles - Clinical Senior Lecturer)
This has been a successful year for the Clinical Trials Group, with the completion of two studies in testis cancer and the publication of four pieces of Orchid sponsored peer reviewed work (two in the British Journal of Cancer, and two in the Annals of Oncology, and one in the New England Journal of Medicine). Dr Powles chaired the prostate cancer session for the ASCO meeting in Chicago, which is the world’s most prestigious cancer forum, and Dr Shamash chaired the influential UK NCRN prostate cancer session in Birmingham. Recruitment into existing NCRN and non NCRN investigator trials continues apace and a number of new studies to replace the completed ones are in design.
1. Studies relating to patients with early testicular and prostate disease
Improved treatment for stage 1 seminoma testicular cancer. Following the International, multi-centre MRC trial, involving 1495 patients, demonstrating that administration of carboplatin for one day (instead of radiotherapy treatment for 3 weeks) was equally effective, less toxic and unexpectedly reduced the second testis tumour incidence by 78% after 5 years of follow up (Lancet 2005 vol 366, page 293-300), Dr Powles has begun a systematic review of late events after 10-15 years in the 200 patients treated in the original Orchid-funded study that led to the MRC trial. This work, published in the Annals of Oncology 2008 vol 19 page 443-7, demonstrates the continued safety of the carboplatin treatment but raises some questions whether the early reduction in second testis cancers seen at 5 years is permanent.
Intermittent hormone therapy (IHT) in hormone sensitive prostate cancer. The results of a meta-analysis of 1446 patients from 12 published studies of IHT were published in the British Journal of Urology vol 99 page 1056-65. Important because of the increasingly recognised ill-effects from prolonged hormone therapy, it concluded that cyclical IHT was safe and that, depending on the level of PSA and speed of response, use of as little as 3 months of treatment was able to show that 1/3rd of patients remain off treatment for 2 or more years. At the same time, it identified that the 1/3rd of patients who, by early recurrence of PSA at less than 12 months, are at risk of hormone resistance, could be candidates for more intense treatment.
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2. Studies into patients with metastatic testis cancer
Patients with good risk but advanced testicular teratoma. The CTAAC funded multi-centre NCRN study of Bleomycin infusion within BEP is recruiting well. Interim analysis is underway and expects to finish within 2 years. Dr Shamash is the Chief Investigator of this work
Patients with good risk metastatic seminoma. Interim analysis of the single agent carboplatin AUC10 study has shown promising results, justifying the plan to move forward to full recruitment. Dr Shamash is the Chief investigator of this work.
Completion and publication of the GAMEC trial in the British Journal of Cancer. The trial had good results in patients with relapsed testis cancer, further questioning the need for high dose therapy in this setting.
Completion and publication in the Annals of Oncology of the IPO trial for patients with multiple relapsed testis cancer. The IPO regimen, which uses previously untried drugs, has very impressive results and a randomised study is planned to take this forward.
Work to investigate prognostic factors associated with poor survival in patients with relapsed testis cancer has been done in collaboration with George Bayer from Germany and has been accepted for publication in the New England Journal of Medicine.
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3. Studies into patients with metastatic hormone-resistant prostate cancer
Last year Orchid supported a trial, now running under the auspices of the NCRN, suggesting that treatment of these patients with Dexamethasone might sensitise their tumour cells to respond better to the oestrogenic steroid, Stilboestrol. Recruitment is accelerating and should be complete in 2008. Dr Shamash is the Chief Investigator of this work.
The Orchid group has continued to pursue the principle of intermittent hormone therapy during chemotherapy for metastatic prostate cancer. This work has been accepted for publication with the British Journal of Cancer and was the topic of the Editorial in that Journal written by Professor Waxman.
The molecular cause of hormone resistance is being studied in collaboration with Dr Prowse, using cancer cells isolated from the patients’ blood. This is under review for publication.
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SCIENTIFIC RESEARCH
Histopathology Programme (Dr Dan Berney)
Histopathology is the microscopic examination of tissue, after sections of a surgical specimen derived from a biopsy has been processed and placed onto glass slides, to establish the presence of disease.
The histopathology or ‘Tissue’ group has had a successful 06/07 with the publication of 8 papers and reviews, and another 5 accepted for publication, indicative of the quantity and quality of its output in this key discipline. Much work has been conducted in collaboration with the other Orchid funded research programmes, providing tissue and pathological support:
Prostate: The clinical studies of watchful waiting prostate cancer, in collaboration with Jonathan Shamash, are now in press or published and the molecular translational work, with Yong Jie Lu, is nearing completion with initial papers and abstracts to be submitted next year. Dr Berney’s reviews of Gleason grading have attracted widespread interest in the urological community. Articles have been published in European Urology, The British Journal of Cancer, The British Journal of Urology (2 articles) and Histopathology (2 articles)
Testis: Dr Berney presented his work on testis tumours in the elderly at a prestigious meeting in San Diego, and the work is to be published in an American journal, Modern Pathology, as well as a prestigious ‘best practice’ review article in The Journal of Clinical Pathology. He was an invited speaker on testis cancer at the British Pathological Society
Penis: A large programme of research has been initiated, with the help of an external grant, into penile cancer. The initial work has already been presented at an international meeting, and the Orchid tissue bank now has the largest collection of penile cancers in a tissue array in Europe, ready for use in future projects.
Molecular Therapeutics Programme (Dr Yong Jie Lu, Senior Lecturer)
This programme focuses on identifying genetic mechanisms of cancer development and chemo-resistance, and attempting to translate them into new therapies.
Testis: Following Dr Lu’s previous work using micro-arrays to screen testicular germ cell tumours across the genome spectrum, for genes involved in chemo-resistance, a number of genes were selected and investigated for their potential in re-sensitising the resistant cancer cells. Switching off one specific gene has been proven to increase cell death (which occurs in normal cells) when treated with the therapeutic drug cisplatin. Further genetic analysis using Single Nucleotide Polymorphism (SNP) microarrays also identified another gene, loss of whose function may be generally associated with testicular cancer development.
Prostate: Arising out of previously reported work, Dr Lu has confirmed two high frequency genetic markers for prostate cancer. The presence of one of the markers has been detected in cancer cells circulating in the blood system, which means that cancer metastasis may be monitored by blood test of the fusion gene. His team has also developed a novel genetic study approach which will accelerate the biomarker discovery in human cancers, and thereby improve/accelerate cancer treatment strategy.
Achievements this year have seen papers published in Genes Chromosomes Cancer, the Journal of Urology, Prostate Cancer Prostatic Diseases, and Current Genomics and more have been submitted, or are in preparation, for publication.
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Carcinogenesis Programme (Dr. David Prowse, Senior Lecturer)
Carcinogenesis, meaning literally the creation of cancer, results from disruption to the regulation of the normal balance between the proliferation and death of cells. This disruption is caused by the mutation of the genetic material of normal cells, which results in uncontrolled cell division and tumor formation.
Following his success in securing his academic position within the Barts & London School of Medicine from July 2007, Dr Prowse has developed his research programme in prostate and penile cancer, with the main aim of understanding and targeting the molecular events involved in the development and progression of these diseases. In particular, current studies focus on the identification and functional analysis of prostate and penile cancer biomarkers, the development and treatment of androgen independent prostate cancer, the role of prostate cancer cells with stem cell characteristics and the analysis of prostate circulating tumour cells, in order to enable non-invasive diagnosis and monitoring of clinical trial patients.
The highlights of this year’s research initiatives were:
The publication of research showing that high risk HPV 16 infection predominates in pre-malignant and malignant penile lesions and it is likely to be an aetiological agent in the development of a significant proportion of penile cancers. These results are important as prophylatic HPV vaccines being developed for prevention of cervical cancer in women could also prevent penile cancers in men.
The finding that PTCH positive circulating prostate tumour cells can be identified in the blood of patients with androgen independent prostate cancer suggests that systemic anti-Hedgehog signalling pathway medicines have potential to be used in the treatment of prostate cancer.
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Pharmacology Programme (Dr Simon Joel, Senior Lecturer)
Pharmacokinetics is the branch of pharmacology that studies what the body does to a drug. This programme aims to improve treatment outcomes by investigating variability in drug pharmacokinetics between patients, and whether this explains differences in efficacy or toxicity for specific combinations of chemotherapy agents. This is becoming a very popular topic and an important area of study.
The first study investigated the pharmacokinetics of cytotoxic drugs used as a salvage treatment regime for poor risk testicular cancer patients in the GAMEC clinical study (see above). Also investigated is the molecular pharmacology of cytotoxic chemotherapy, including novel agents and established drugs. This work has two main areas of interest: firstly, platinum sensitivity and resistance in testicular tumour cell lines, in collaboration with Dr Yong Jie Lu, and secondly, the impact of new drugs that target MDM2, thereby enhancing or prolonging the activity of an important nuclear protein, p53, and the effect of this on chemo-sensitivity.
Achievements over the past year have seen two sets of data presented at the NCRI meeting in Oct 06: one detailed the inhibition of MDM2 using antisense and small drug molecule approaches (and was also presented at the American Association for Cancer Research meeting in Los Angeles in Apr 07); the second reported Actinomycin D pharmacokinetic data from the GAMEC trial, which has been published in the BJC. In addition, further evaluation is underway (with Dr Lu) of protein changes associated with cisplatin sensitivity in TGCT sensitive and resistant cell line pairs.
Summary
In summary, the research teams are producing exciting results, which have been presented in national and international forums and publications. Their work has resulted in better treatment as well as offering significant potential for improving survival and quality of life for male cancer patients.
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