Circulating Tumour Cell Enumeration and Molecular Evaluation in Patients with Advanced Prostate Carcinoma.
Lead Research Organisation:
Institute of Cancer Research
Department Name: Medicine
Abstract
Prostate cancer is the second commonest cause of death from cancer in men. Little progress has been made in the treatment of this disease since testicular testosterone deprivation was identified as a therapeutic modality. There is an urgent need to accelerate the development of novel therapies for this disease. Key bottlenecks to the treatment of this disease include poor clinical predictors of which drugs result in clinical benefit, and lack of access to hormone resistant cancer cells to understand the biology of the disease. This results in protracted trials, lasting many years, evaluating whether new treatments prolong time to death of large numbers of patients. It is envisioned that the enumeration, separation and study of prostate cancer cells in the blood of patients using validated new technology will expedite clinical trials and allow access to tumour cells for the study of the biology of this disease, leading to improvements in treatment for this unmet need.
Technical Summary
Circulating tumour cells (CTC) can be reliably quantitated by the CellTracks? System (Immunicon, PA), which allows the automated detection and isolation of rare cancer cells from blood to GCLP. CTC are not detected in healthy subjects or in non-malignant diseases. In breast cancer, CTC counts predict outcome and response to therapy (FDA approved test).
CTC are detected most frequently in prostate cancer patients. We have studied CTC in over 300 men with castration refractory prostate cancer (CRPC), with CTC being detected in 60-70% of men (Median 5 CTC/7.5 mls blood; Range: 0-6000 CTC). These studies indicate that in CRPC, CTC counts predict survival. We have successfully characterized CTC by immunofluorescence for protein expression and by FISH for DNA amplification and TMPRSS2/ETS gene translocations.
These findings are of critical importance since in CRPC access to tumour tissue is not usually feasible. Moreover, most patients do not have measurable disease, with treatment decisions being based on PSA levels. Better predictors of clinical benefit such as CTC counts are urgently needed to improve outcome. Repeated access to CTC for molecular analysis also provides a powerful tool for identifying molecular markers of response and resistance.
Hypothesis
1. CTC count changes predict clinical benefit from treatment in patients with CRPC.
2. CTCs can be molecularly characterised and can be utilized for biomarker studies in clinical trials of rationally designed, molecularly targeted drugs.
3. Molecular changes induced by targeted drugs, or at disease progression, can be detected in CTC, and can impact anticancer drug development in CRPC patients.
Proposal: We propose the study of CTC in patients with CRPC, focusing on forthcoming randomised studies of a small molecule inhibitor of androgen synthesis generated at this institution, and now outlicensed to Cougar Biotechnology. This small molecule, abiraterone, irreversibly inhibits CYP17 and in ongoing trials has minimal toxicity and impressive antitumour activity (over 50% PSA decline rate: 70%) in CRPC patients failing all known hormonal therapies including LHRH analogues, androgen antagonists, steroids, ketoconazole and diethystilboestrol.
Key aims:
1.To evaluate whether CTC counts can be utilized as surrogates of clinical benefit in therapeutic trials for CRPC patients.
2. To evaluate the utility of the molecular characterization of CTCs in the treatment of CRPC patients with molecularly targeted drugs
3. To determine mechanisms of drug resistance by studying CTCs.
Implications: It is envisioned that this work will accelerate clinical drug development for advanced prostate cancer patients, leading to improved treatment of an unmet clinical need.
CTC are detected most frequently in prostate cancer patients. We have studied CTC in over 300 men with castration refractory prostate cancer (CRPC), with CTC being detected in 60-70% of men (Median 5 CTC/7.5 mls blood; Range: 0-6000 CTC). These studies indicate that in CRPC, CTC counts predict survival. We have successfully characterized CTC by immunofluorescence for protein expression and by FISH for DNA amplification and TMPRSS2/ETS gene translocations.
These findings are of critical importance since in CRPC access to tumour tissue is not usually feasible. Moreover, most patients do not have measurable disease, with treatment decisions being based on PSA levels. Better predictors of clinical benefit such as CTC counts are urgently needed to improve outcome. Repeated access to CTC for molecular analysis also provides a powerful tool for identifying molecular markers of response and resistance.
Hypothesis
1. CTC count changes predict clinical benefit from treatment in patients with CRPC.
2. CTCs can be molecularly characterised and can be utilized for biomarker studies in clinical trials of rationally designed, molecularly targeted drugs.
3. Molecular changes induced by targeted drugs, or at disease progression, can be detected in CTC, and can impact anticancer drug development in CRPC patients.
Proposal: We propose the study of CTC in patients with CRPC, focusing on forthcoming randomised studies of a small molecule inhibitor of androgen synthesis generated at this institution, and now outlicensed to Cougar Biotechnology. This small molecule, abiraterone, irreversibly inhibits CYP17 and in ongoing trials has minimal toxicity and impressive antitumour activity (over 50% PSA decline rate: 70%) in CRPC patients failing all known hormonal therapies including LHRH analogues, androgen antagonists, steroids, ketoconazole and diethystilboestrol.
Key aims:
1.To evaluate whether CTC counts can be utilized as surrogates of clinical benefit in therapeutic trials for CRPC patients.
2. To evaluate the utility of the molecular characterization of CTCs in the treatment of CRPC patients with molecularly targeted drugs
3. To determine mechanisms of drug resistance by studying CTCs.
Implications: It is envisioned that this work will accelerate clinical drug development for advanced prostate cancer patients, leading to improved treatment of an unmet clinical need.