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Direct effects of the selective CYP17 lyase (L) inhibitor, VT-464, on the androgen receptor (AR) and its oral activity in an F876L tumor mouse xenograft model.

Publication ,  Conference
Moore, WR; Norris, JD; Wardell, S; Eisner, JR; Hoekstra, WJ; Schotzinger, RJ; McDonnell, DP
Published in: Journal of Clinical Oncology
March 1, 2015

263 Background: MDV3100 inhibits binding of androgens to AR and abiraterone is known to block androgen production through CYP17 inhibition; both are effective treatments for castration-resistant prostate cancer (CRPC, yet cross-resistance to both agents is problematic. The AR mutations F876L and T877A increase resistance to MDV3100 (M) or abiraterone (A), respectively. A regimen resistance is likely mediated through T877A activation by stimulatory progesterone (P4), pregnenolone (P5), or prednisone. The oral, non-steroidal L-inhibitor, VT-464, in phase 2 CRPC studies without prednisone coadministration, does not increase P4 or P5. Methods: The effects of VT-464, A, and M on AR transcription activity and cell proliferation were assessed and compared using reporter assays, and their oral effects in an M-resistant (F876L) human tumor mouse model were also assessed. Results: VT-464 competitively antagonized (Schild analysis) wild-type AR (IC50 =18 µM) and its potency was not decreased by AR overexpression (VCaP IC50=7.4μM). VT-464 fully antagonized AR T877A (IC50=0.52 μM) and inhibited LNCaP cell (AR T877A mutation) proliferation (IC50=0.70 μM) with potency similar to M. In contrast to M, VT-464 fully inhibited F876L (IC50=2.5 μM). VT-464 did not activate any AR forms up to the highest concentration tested (60 μM). In vivo, greater F876L tumor inhibition was observed with oral VT-464 compared to oral M or abiraterone acetate. Conclusions: VT-464 more potently antagonized mutated AR forms associated with A or M resistance than wild-type; AR antagonism contributed to xenograft activity and appears relevant to its clinical pharmacology. Due to its high L inhibition selectivity and potent mutant AR antagonist activity, VT-464 has a suitable profile for the treatment of early- or late-stage CRPC patients. VT-464 has advanced into phase 2 studies funded by Innocrin (NCT#02012920), the NCI (NCT02130700), and PCF in M- and A-resistant populations.

Duke Scholars

Published In

Journal of Clinical Oncology

DOI

EISSN

1527-7755

ISSN

0732-183X

Publication Date

March 1, 2015

Volume

33

Issue

7_suppl

Start / End Page

263 / 263

Publisher

American Society of Clinical Oncology (ASCO)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 1112 Oncology and Carcinogenesis
  • 1103 Clinical Sciences
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Moore, W. R., Norris, J. D., Wardell, S., Eisner, J. R., Hoekstra, W. J., Schotzinger, R. J., & McDonnell, D. P. (2015). Direct effects of the selective CYP17 lyase (L) inhibitor, VT-464, on the androgen receptor (AR) and its oral activity in an F876L tumor mouse xenograft model. In Journal of Clinical Oncology (Vol. 33, pp. 263–263). American Society of Clinical Oncology (ASCO). https://doi.org/10.1200/jco.2015.33.7_suppl.263
Moore, William R., John D. Norris, Suzanne Wardell, Joel Robert Eisner, William J. Hoekstra, Robert J. Schotzinger, and Donald P. McDonnell. “Direct effects of the selective CYP17 lyase (L) inhibitor, VT-464, on the androgen receptor (AR) and its oral activity in an F876L tumor mouse xenograft model.” In Journal of Clinical Oncology, 33:263–263. American Society of Clinical Oncology (ASCO), 2015. https://doi.org/10.1200/jco.2015.33.7_suppl.263.
Moore WR, Norris JD, Wardell S, Eisner JR, Hoekstra WJ, Schotzinger RJ, et al. Direct effects of the selective CYP17 lyase (L) inhibitor, VT-464, on the androgen receptor (AR) and its oral activity in an F876L tumor mouse xenograft model. In: Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO); 2015. p. 263–263.
Moore, William R., et al. “Direct effects of the selective CYP17 lyase (L) inhibitor, VT-464, on the androgen receptor (AR) and its oral activity in an F876L tumor mouse xenograft model.Journal of Clinical Oncology, vol. 33, no. 7_suppl, American Society of Clinical Oncology (ASCO), 2015, pp. 263–263. Crossref, doi:10.1200/jco.2015.33.7_suppl.263.
Moore WR, Norris JD, Wardell S, Eisner JR, Hoekstra WJ, Schotzinger RJ, McDonnell DP. Direct effects of the selective CYP17 lyase (L) inhibitor, VT-464, on the androgen receptor (AR) and its oral activity in an F876L tumor mouse xenograft model. Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO); 2015. p. 263–263.

Published In

Journal of Clinical Oncology

DOI

EISSN

1527-7755

ISSN

0732-183X

Publication Date

March 1, 2015

Volume

33

Issue

7_suppl

Start / End Page

263 / 263

Publisher

American Society of Clinical Oncology (ASCO)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 1112 Oncology and Carcinogenesis
  • 1103 Clinical Sciences