Anticancer Activity of a Novel Selective CYP17A1 Inhibitor in Preclinical Models of Castrate-Resistant Prostate Cancer
Paul Toren,Soojin Kim,Steven Pham,Azzra Mangalji,Hans Adomat,Emma S. Tomlinson Guns,Amina Zoubeidi,William R. Moore,Martin E. Gleave +8 more
TLDR
Preclinical results suggest greater suppression of the AR axis with VT-464 than ABI that is likely due to both superior selective suppression of androgen synthesis and AR antagonism.Abstract:
VT-464 is a novel, nonsteroidal, small-molecule CYP17A1 inhibitor with 17,20-lyase selectivity. This study evaluates the anticancer activity of VT-464 compared with abiraterone (ABI) in castrate-resistant prostate cancer cell lines and xenograft models that are enzalutamide (ENZ)-responsive (C4-2) or ENZ-resistant (MR49C, MR49F). In vitro, androgen receptor (AR) transactivation was assessed by probasin luciferase reporter, whereas AR and AR-regulated genes and steroidogenic pathway enzymes were assessed by Western blot and/or qRT-PCR. The MR49F xenograft model was used to compare effects of oral VT-464 treatment to vehicle and abiraterone acetate (AA). Steroid concentrations were measured using LC-MS chromatography. VT-464 demonstrated a greater decrease in AR transactivation compared with ABI in C4-2 and both ENZ-resistant cell lines. At the gene and protein level, VT-464 suppressed the AR axis to a greater extent compared with ABI. Gene transcripts StAR, CYP17A1, HSD17B3, and SRD5A1 increased following treatment with ABI and to a greater extent with VT-464. In vivo, intratumoral androgen levels were significantly lower after VT-464 or AA treatment compared with vehicle, with the greatest decrease seen with VT-464. Similarly, tumor growth inhibition and PSA decrease trends were greater with VT-464 than with AA. Finally, an AR-antagonist effect of VT-464 independent of CYP17A1 inhibition was observed using luciferase reporter assays, and a direct interaction was confirmed using an AR ligand binding domain biolayer interferometry. These preclinical results suggest greater suppression of the AR axis with VT-464 than ABI that is likely due to both superior selective suppression of androgen synthesis and AR antagonism.read more
Citations
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Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients
Nada Lallous,Stanislav Volik,Shannon Awrey,Eric Leblanc,Ronnie Tse,Josef Murillo,Kriti Singh,Arun Azad,Alexander W. Wyatt,Stephane LeBihan,Kim N. Chi,Martin E. Gleave,Paul S. Rennie,Colin Collins,Artem Cherkasov +14 more
TL;DR: The feasibility of a prognostic and/or diagnostic platform combining the direct identification of AR mutants from patients’ serum, and the functional characterization of these mutants in order to provide personalized recommendations regarding the best future therapy is demonstrated.
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Androgen receptor function and androgen receptor–targeted therapies in breast cancer: A review
TL;DR: In-depth understanding of AR and AR-related signaling pathways would improve the treatment strategies for AR-positive breast cancer and inform the development of AR-targeted therapies to improve survival outcome in patients with breast cancer.
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Targeting the adaptive molecular landscape of castration-resistant prostate cancer
TL;DR: The heterogeneous and evolvable molecular landscape of CRPC is described and recent successes and failures of therapeutic strategies designed to target AR reactivation and adaptive survival pathways are explored.
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Intersection of the Roles of Cytochrome P450 Enzymes with Xenobiotic and Endogenous Substrates: Relevance to Toxicity and Drug Interactions
TL;DR: Today much is known about cytochrome P450 (P450) enzymes and their catalytic specificity, but the range of reactions catalyzed by each still continues to surprise and the line of demarcation is sometimes blurred.
References
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Journal ArticleDOI
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.
Journal ArticleDOI
Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy
Howard I. Scher,Karim Fizazi,Fred Saad,Mary-Ellen Taplin,Cora N. Sternberg,Kurt Miller,Ronald de Wit,Peter F.A. Mulders,Kim N. Chi,Neal D. Shore,Andrew J. Armstrong,Thomas W. Flaig,Aude Flechon,Paul N. Mainwaring,Mark D. Fleming,John D. Hainsworth,Mohammad Hirmand,Bryan Selby,Lynn Seely,Johann S. de Bono,B Ch +20 more
TL;DR: Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy, and was shown with respect to all secondary end points.
Journal ArticleDOI
Glucocorticoid Receptor Confers Resistance to Antiandrogens by Bypassing Androgen Receptor Blockade
Vivek K. Arora,Emily Schenkein,Rajmohan Murali,Sumit K. Subudhi,John Wongvipat,Minna D. Balbas,Neel Shah,Ling Cai,Eleni Efstathiou,Chris Logothetis,Deyou Zheng,Charles L. Sawyers,Charles L. Sawyers +12 more
TL;DR: This work identifies induction of glucocorticoid receptor (GR) expression as a common feature of drug-resistant tumors in a credentialed preclinical model and establishes a mechanism of escape from AR blockade through expansion of cells primed to drive AR target genes via an alternative nuclear receptor upon drug exposure.
Journal ArticleDOI
Resistance to CYP17A1 inhibition with abiraterone in castration resistant prostate cancer: Induction of steroidogenesis and androgen receptor splice variants
Elahe A. Mostaghel,Brett T. Marck,Stephen R. Plymate,Robert L. Vessella,Stephen P. Balk,Alvin M. Matsumoto,Peter S. Nelson,R. Bruce Montgomery +7 more
TL;DR: It is indicated that abiraterone reduces CRPC growth via suppression of intratumoral androgens and that resistance to abIRaterone may occur through mechanisms that include upregulation of CYP17A1, and/or induction of AR and AR splice variants that confer ligand-independent AR transactivation.
Journal ArticleDOI
A Clinically Relevant Androgen Receptor Mutation Confers Resistance to Second-Generation Antiandrogens Enzalutamide and ARN-509
James Joseph,Nhin Lu,Jing Qian,John Sensintaffar,Gang Shao,Dan Brigham,Michael Moon,Edna Chow Maneval,Isan Chen,Beatrice Darimont,Jeffrey H. Hager +10 more
TL;DR: A missense mutation in the ligand-binding domain of the androgen receptor F876L confers resistance to the second-generation antiandrogens enzalutamide and ARN-509 in preclinical models of AR function and prostate cancer and is detected in plasma DNA from ARn-509-treated patients with progressive disease.
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