Targeting CYP17: established and novel approaches in prostate cancer.
ABSTRACT There is a growing body of evidence that although medical or surgical castration blocks the generation of gonadal testosterone in prostate cancer, androgens originating from other sources may continue to drive androgen receptor (AR) signaling. Recent studies have demonstrated high intratumoral levels of androgens and continued AR signaling in castration-resistant prostate cancer (CRPC), suggesting that androgens may also be synthesized de novo. Inhibiting the systemic biosynthesis of androgens in CRPC by targeting CYP17 may thus represent a rational therapeutic approach since this enzyme catalyses two key steroid reactions involving 17alpha-hydroxylase and C(17,20)-lyase in the androgen biosynthesis pathway. This review will discuss the rationale for and implications of targeting CYP17 in CRPC and focus on established and novel CYP17 inhibitors, including ketoconazole, abiraterone acetate, and VN/124-1, which are agents currently at different stages of development.
- SourceAvailable from: Antimo Migliaccio[Show abstract] [Hide abstract]
ABSTRACT: Prostate cancer is the second leading cause of cancer death in men in the US. The initial treatment of metastatic prostate cancer is androgen deprivation (castration) therapy and this is achieved through either surgical or medical castration, however these therapies are also associated with undesirable side effects including impotence, tumour flare and loss of bone mass. Over time, nearly all patients with metastatic disease become resistant to androgen deprivation, progressing to castration-resistant prostate cancer (CRPC), and at this stage of the disease the prognosis is extremely poor (<50 % survival at two years). Currently there are few treatment options for CRPC. Only four have been found to extend survival and none are curative. Effective treatment of CRPC is a major unmet clinical need, and the identification of alternative therapeutic targets is an active focus of research. In this article we discuss the development of a new agent, Val 201 as a potential future treatment for CRPC. VAL 201 targets the association of androgen receptor with Src, a non-receptor tyrosine kinase signal-transduction protein that is important in tumour cell proliferation, and represents a novel and exciting approach for cancer chemotherapy.
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ABSTRACT: Prostate cancer remains the most common type of cancer among men in the United States. Treatment for metastatic prostate cancer has improved significantly over the years with more and more agents improving overall survival. This review will address the pathophysiology of prostate cancer followed by the mechanism of action and the pharmacokinetic properties of abiraterone. The review will also discuss the role of abiraterone in the treatment of metastatic castrate-resistant prostate cancer.Research and reports in urology. 01/2014; 6:97-105.
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ABSTRACT: Introduction Abiraterone (AA) is a CYP17 inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC). Data suggest similar pharmacokinetics of 250–500 mg of AA with high-fat meals (‘low-dose’) and 1000 mg in the fasting state (‘full-dose’). Ketoconazole (KT) is a less potent CYP17 inhibitor previously widely used in mCRPC. Objective To study outcomes of men with mCRPC treated with low-dose AA and/or with prior exposure to KT. Patients and methods Retrospective chart review of all men treated with AA at the Princess Margaret Cancer Centre between November 2009 and March 2013. Outcome measures were prostate-specific antigen response rate (PSA-RR), biochemical progression-free survival (bPFS), treatment duration and overall survival (OS). Associations between AA dose or prior KT and outcomes were assessed using chi-square test for PSA-RR and log-rank test for bPFS, treatment duration and OS. Results In total, 111 men who received AA were evaluable, of which 21 received low-dose AA and 23 received prior KT. There was a non-significant difference in PSA-RR (43% versus 32%, p = 0.37), but no significant differences in median bPFS, median treatment duration and median OS (18.7 versus 16.6 months, p = 0.25) in the full and low-dose cohorts respectively, and for those who received prior KT or not (PSA-RR 48% versus 38%, p = 0.4; median OS 24.2 versus 16.5 months, p = 0.066, respectively). Conclusions Low-dose AA or prior KT treatment were not associated with poorer outcome in men with mCRPC treated with AA. These observations may have implications for drug sequencing and dose in resource-limited settings.European Journal of Cancer 09/2014; · 4.82 Impact Factor