Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy.
Zhenfei Li,Mohammad Alyamani,Jianneng Li,Kevin Rogacki,Mohamad E. Abazeed,Sunil K. Upadhyay,Steven P. Balk,Mary-Ellen Taplin,Richard J. Auchus,Nima Sharifi +9 more
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TLDR
The findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy, and demonstrate the specific biochemical effects of pharmacological 5α-reductase inhibition on abiraters metabolism.Abstract:
Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis. Abiraterone is metabolized in patients to Δ(4)-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is converted to at least three 5α-reduced and three 5β-reduced metabolites in human serum. The initial 5α-reduced metabolite, 3-keto-5α-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumour-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy.read more
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Journal ArticleDOI
Androgen Signaling in Prostate Cancer
TL;DR: Current understanding of AR signaling as it pertains to the biology and natural history of prostate cancer is reviewed.
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Transdifferentiation as a Mechanism of Treatment Resistance in a Mouse Model of Castration-Resistant Prostate Cancer
Min Zou,Roxanne Toivanen,Antonina Mitrofanova,Nicolas Floc'h,Sheida Hayati,Yanping Sun,Clémentine Le Magnen,Daniel Chester,Elahe A. Mostaghel,Andrea Califano,Mark A. Rubin,Michael M. Shen,Cory Abate-Shen +12 more
TL;DR: Novel insights into treatment response for the antiandrogen abiraterone are provided by analyses of a genetically engineered mouse model with combined inactivation of Trp53 and Pten, which are frequently comutated in human CRPC.
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Treatment of Advanced Prostate Cancer—A Review of Current Therapies and Future Promise
TL;DR: The development of next-generation sequencing techniques and the routine biopsy of metastatic disease have driven significant advances in the understanding of the genomics of cancer, and are now poised to transform the treatment of this disease.
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HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study
Jason W.D. Hearn,Ghada AbuAli,Chad A. Reichard,Chandana A. Reddy,Cristina Magi-Galluzzi,Kai Hsiung Chang,Rachel Carlson,Laureano J. Rangel,Kevin Reagan,Brian J. Davis,R. Jeffrey Karnes,Manish Kohli,Donald J. Tindall,Eric A. Klein,Nima Sharifi,Nima Sharifi +15 more
TL;DR: HSD3B1 could potentially be a powerful genetic biomarker capable of distinguishing men who are a priori likely to fare favourably with ADT from those who harbour disease liable to behave more aggressively, and who therefore might warrant early escalated therapy.
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Abiraterone and Increased Survival in Metastatic Prostate Cancer
Johann S. de Bono,Christopher J. Logothetis,Arturo Molina,Karim Fizazi,Scott North,Luis Chu,Kim N. Chi,Robert Jones,Oscar B. Goodman,Fred Saad,John Staffurth,Paul N. Mainwaring,S. J. Harland,Thomas W. Flaig,Thomas E. Hutson,Tina Cheng,Helen Patterson,John D. Hainsworth,Charles J. Ryan,Cora N. Sternberg,Susan Ellard,Aude Flechon,Mansoor N. Saleh,Mark C. Scholz,Eleni Efstathiou,Andrea Zivi,Diletta Bianchini,Yohann Loriot,Nicole Chieffo,Thian Kheoh,Christopher M. Haqq,Howard I. Scher +31 more
TL;DR: The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy.
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