{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T08:38:23Z","timestamp":1789720703725,"version":"4.0.1"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,10,17]],"date-time":"2016-10-17T00:00:00Z","timestamp":1476662400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,10,17]],"date-time":"2016-10-17T00:00:00Z","timestamp":1476662400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Cytochrome P450 17\u03b1-hydroxylase\/17,20-lyase (CYP17A1) is a validated treatment target for the treatment of metastatic castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA) inhibits both 17\u03b1-hydroxylase (hydroxylase) and 17,20-lyase (lyase) reactions catalyzed by CYP17A1 and thus depletes androgen biosynthesis. However, coadministration of prednisone is required to suppress the mineralocorticoid excess and cortisol depletion that result from hydroxylase inhibition. VT-464, a nonsteroidal small molecule, selectively inhibits CYP17A1 lyase and therefore does not require prednisone supplementation. Administration of VT-464 in a metastatic CRPC patient presenting with high tumoral expression of both androgen receptor (AR) and CYP17A1, showed significant reduction in the level of both dehydroepiandrosterone (DHEA) and serum PSA. Treatment of a CRPC patient-derived xenograft, MDA-PCa-133 expressing H874Y AR mutant with VT-464, reduced the increase in tumor volume in castrate male mice more than twice as much as the vehicle (P\u2009&lt;\u20090.05). Mass spectrometry analysis of post-treatment xenograft tumor tissues showed that VT-464 significantly decreased intratumoral androgens but not cortisol. VT-464 also reduced AR signaling more effectively than abiraterone in cultured PCa cells expressing T877A AR mutant. Collectively, this study suggests that VT-464 therapy can effectively treat CRPC and be used in precision medicine based on androgen receptor mutation status.<\/jats:p>","DOI":"10.1038\/srep35354","type":"journal-article","created":{"date-parts":[[2016,10,17]],"date-time":"2016-10-17T11:10:48Z","timestamp":1476702648000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Targeting of CYP17A1 Lyase by VT-464 Inhibits Adrenal and Intratumoral Androgen Biosynthesis and Tumor Growth of Castration Resistant Prostate Cancer"],"prefix":"10.1038","volume":"6","author":[{"given":"Sankar N.","family":"Maity","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Titus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Revekka","family":"Gyftaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanglin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Fang","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Ramachandran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elsa M.","family":"Li-Ning-Tapia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Logothetis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Araujo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Efstathiou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,10,17]]},"reference":[{"key":"BFsrep35354_CR1","doi-asserted-by":"publisher","first-page":"1995","DOI":"10.1056\/NEJMoa1014618","volume":"364","author":"JS de Bono","year":"2011","unstructured":"de Bono, J. S. et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364, 1995\u20132005, 10.1056\/NEJMoa1014618 (2011).","journal-title":"N Engl J Med"},{"key":"BFsrep35354_CR2","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1200\/JCO.2010.33.7675","volume":"30","author":"E Efstathiou","year":"2012","unstructured":"Efstathiou, E. et al. Effects of abiraterone acetate on androgen signaling in castrate-resistant prostate cancer in bone. J Clin Oncol 30, 637\u2013643, 10.1200\/JCO.2010.33.7675 (2012).","journal-title":"J Clin Oncol"},{"key":"BFsrep35354_CR3","doi-asserted-by":"publisher","first-page":"3353","DOI":"10.1158\/1078-0432.CCR-12-0931","volume":"19","author":"R Ferraldeschi","year":"2013","unstructured":"Ferraldeschi, R., Sharifi, N., Auchus, R. J. & Attard, G. Molecular pathways: Inhibiting steroid biosynthesis in prostate cancer. Clin Cancer Res 19, 3353\u20133359, 10.1158\/1078-0432.CCR-12-0931 (2013).","journal-title":"Clin Cancer Res"},{"key":"BFsrep35354_CR4","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1002\/pros.23146","volume":"76","author":"M Sakai","year":"2016","unstructured":"Sakai, M., Martinez-Arguelles, D. B., Aprikian, A. G., Magliocco, A. M. & Papadopoulos, V. De novo steroid biosynthesis in human prostate cell lines and biopsies. Prostate 76, 575\u2013587, 10.1002\/pros.23146 (2016).","journal-title":"Prostate"},{"key":"BFsrep35354_CR5","doi-asserted-by":"publisher","first-page":"5375","DOI":"10.1021\/jm981017j","volume":"41","author":"M Jarman","year":"1998","unstructured":"Jarman, M., Barrie, S. E. & Llera, J. M. The 16,17-double bond is needed for irreversible inhibition of human cytochrome p45017alpha by abiraterone (17-(3-pyridyl)androsta-5, 16-dien-3beta-ol) and related steroidal inhibitors. J Med Chem 41, 5375\u20135381, 10.1021\/jm981017j (1998).","journal-title":"J Med Chem"},{"key":"BFsrep35354_CR6","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1056\/NEJMoa1209096","volume":"368","author":"CJ Ryan","year":"2013","unstructured":"Ryan, C. J. et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 368, 138\u2013148, 10.1056\/NEJMoa1209096 (2013).","journal-title":"N Engl J Med"},{"key":"BFsrep35354_CR7","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1016\/S1470-2045(12)70473-4","volume":"13","author":"CJ Logothetis","year":"2012","unstructured":"Logothetis, C. J. et al. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol 13, 1210\u20131217, 10.1016\/S1470-2045(12)70473-4 (2012).","journal-title":"Lancet Oncol"},{"key":"BFsrep35354_CR8","doi-asserted-by":"crossref","unstructured":"Rafferty, S. W., Eisner, J. R., Moore, W. R., Schotzinger, R. J. & Hoekstra, W. J. Highly-selective 4-(1,2,3-triazole)-based P450c17a 17,20-lyase inhibitors. Bioorg Med Chem Lett, 10.1016\/j.bmcl.2014.04.024 (2014).","DOI":"10.1016\/j.bmcl.2014.04.024"},{"key":"BFsrep35354_CR9","doi-asserted-by":"publisher","first-page":"5913","DOI":"10.1158\/1078-0432.CCR-11-0728","volume":"17","author":"EA Mostaghel","year":"2011","unstructured":"Mostaghel, E. A. et al. Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants. Clin Cancer Res 17, 5913\u20135925, 10.1158\/1078-0432.CCR-11-0728 (2011).","journal-title":"Clin Cancer Res"},{"key":"BFsrep35354_CR10","doi-asserted-by":"publisher","first-page":"1590","DOI":"10.1158\/1078-0432.CCR-13-1863","volume":"20","author":"Z Yu","year":"2014","unstructured":"Yu, Z. et al. Rapid induction of androgen receptor splice variants by androgen deprivation in prostate cancer. Clin Cancer Res 20, 1590\u20131600, 10.1158\/1078-0432.CCR-13-1863 (2014).","journal-title":"Clin Cancer Res"},{"key":"BFsrep35354_CR11","first-page":"1496","volume":"62","author":"XB Shi","year":"2002","unstructured":"Shi, X. B., Ma, A. H., Xia, L., Kung, H. J. & de Vere White, R. W. Functional analysis of 44 mutant androgen receptors from human prostate cancer. Cancer Res 62, 1496\u20131502 (2002).","journal-title":"Cancer Res"},{"key":"BFsrep35354_CR12","doi-asserted-by":"publisher","first-page":"6503","DOI":"10.1158\/0008-5472.CAN-11-0532","volume":"71","author":"C Cai","year":"2011","unstructured":"Cai, C. et al. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors. Cancer Res 71, 6503\u20136513, 10.1158\/0008-5472.CAN-11-0532 (2011).","journal-title":"Cancer Res"},{"key":"BFsrep35354_CR13","doi-asserted-by":"publisher","first-page":"4766","DOI":"10.1128\/MCB.00647-13","volume":"33","author":"L Ni","year":"2013","unstructured":"Ni, L. et al. Androgen induces a switch from cytoplasmic retention to nuclear import of the androgen receptor. Mol Cell Biol 33, 4766\u20134778, 10.1128\/MCB.00647-13 (2013).","journal-title":"Mol Cell Biol"},{"key":"BFsrep35354_CR14","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1158\/1078-0432.CCR-12-3601","volume":"20","author":"EA Mostaghel","year":"2014","unstructured":"Mostaghel, E. A., Plymate, S. R. & Montgomery, B. Molecular pathways: targeting resistance in the androgen receptor for therapeutic benefit. Clin Cancer Res 20, 791\u2013798, 10.1158\/1078-0432.CCR-12-3601 (2014).","journal-title":"Clin Cancer Res"},{"key":"BFsrep35354_CR15","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1158\/0008-5472.CAN-12-3630","volume":"73","author":"Y Li","year":"2013","unstructured":"Li, Y. et al. Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res 73, 483\u2013489, 10.1158\/0008-5472.CAN-12-3630 (2013).","journal-title":"Cancer Res"},{"key":"BFsrep35354_CR16","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.cell.2009.04.056","volume":"138","author":"Q Wang","year":"2009","unstructured":"Wang, Q. et al. Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 138, 245\u2013256, 10.1016\/j.cell.2009.04.056 (2009).","journal-title":"Cell"},{"key":"BFsrep35354_CR17","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/j.ccr.2011.09.001","volume":"20","author":"C Cai","year":"2011","unstructured":"Cai, C. et al. Androgen receptor gene expression in prostate cancer is directly suppressed by the androgen receptor through recruitment of lysine-specific demethylase 1. Cancer Cell 20, 457\u2013471, 10.1016\/j.ccr.2011.09.001 (2011).","journal-title":"Cancer Cell"},{"key":"BFsrep35354_CR18","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1158\/1535-7163.MCT-14-0521","volume":"14","author":"PJ Toren","year":"2015","unstructured":"Toren, P. J. et al. Anticancer Activity of a Novel Selective CYP17A1 Inhibitor in Preclinical Models of Castrate-Resistant Prostate Cancer. Mol Cancer Ther 14, 59\u201369, 10.1158\/1535-7163.MCT-14-0521 (2015).","journal-title":"Mol Cancer Ther"},{"key":"BFsrep35354_CR19","doi-asserted-by":"publisher","first-page":"2176","DOI":"10.1158\/0008-5472.CAN-11-3980","volume":"72","author":"J Richards","year":"2012","unstructured":"Richards, J. et al. Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Res 72, 2176\u20132182, 10.1158\/0008-5472.CAN-11-3980 (2012).","journal-title":"Cancer Res"},{"key":"BFsrep35354_CR20","doi-asserted-by":"publisher","first-page":"3777","DOI":"10.1074\/jbc.M111.261933","volume":"287","author":"HS Soifer","year":"2012","unstructured":"Soifer, H. S. et al. Direct regulation of androgen receptor activity by potent CYP17 inhibitors in prostate cancer cells. J Biol Chem 287, 3777\u20133787, 10.1074\/jbc.M111.261933 (2012).","journal-title":"J Biol Chem"},{"key":"BFsrep35354_CR21","doi-asserted-by":"publisher","first-page":"e32514","DOI":"10.1371\/journal.pone.0032514","volume":"7","author":"CW Hay","year":"2012","unstructured":"Hay, C. W. & McEwan, I. J. The impact of point mutations in the human androgen receptor: classification of mutations on the basis of transcriptional activity. PLoS One 7, e32514, 10.1371\/journal.pone.0032514 (2012).","journal-title":"PLoS One"},{"issue":"14","key":"BFsrep35354_CR22","doi-asserted-by":"publisher","first-page":"3457","DOI":"10.1158\/0008-5472.CAN-11-3892","volume":"72","author":"R. Hu","year":"2012","unstructured":"Hu, R. et al. Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer. Cancer Res 72, 3457\u20133462, 0008-5472.CAN-11-3892 [pii] 10.1158\/0008-5472.CAN-11-3892.","journal-title":"Cancer Research"},{"key":"BFsrep35354_CR23","doi-asserted-by":"publisher","first-page":"16759","DOI":"10.1073\/pnas.1012443107","volume":"107","author":"PA Watson","year":"2010","unstructured":"Watson, P. A. et al. Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc Natl Acad Sci USA 107, 16759\u201316765, 10.1073\/pnas.1012443107 (2010).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep35354_CR24","doi-asserted-by":"publisher","first-page":"3319","DOI":"10.1021\/jm950749y","volume":"39","author":"FC Chan","year":"1996","unstructured":"Chan, F. C. et al. 3- and 4-pyridylalkyl adamantanecarboxylates: inhibitors of human cytochrome P450(17 alpha) (17 alpha-hydroxylase\/C17,20-lyase). Potential nonsteroidal agents for the treatment of prostatic cancer. J Med Chem 39, 3319\u20133323, 10.1021\/jm950749y (1996).","journal-title":"J Med Chem"},{"key":"BFsrep35354_CR25","doi-asserted-by":"publisher","first-page":"2463","DOI":"10.1021\/jm00013a022","volume":"38","author":"GA Potter","year":"1995","unstructured":"Potter, G. A., Barrie, S. E., Jarman, M. & Rowlands, M. G. Novel steroidal inhibitors of human cytochrome P45017 alpha (17 alpha-hydroxylase-C17,20-lyase): potential agents for the treatment of prostatic cancer. J Med Chem 38, 2463\u20132471 (1995).","journal-title":"J Med Chem"},{"key":"BFsrep35354_CR26","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1007\/978-1-61779-243-4_5","volume":"776","author":"H Makkonen","year":"2011","unstructured":"Makkonen, H., Jaaskelainen, T., Rytinki, M. M. & Palvimo, J. J. Analysis of androgen receptor activity by reporter gene assays. Methods Mol Biol 776, 71\u201380, 10.1007\/978-1-61779-243-4_5 (2011).","journal-title":"Methods Mol Biol"},{"key":"BFsrep35354_CR27","doi-asserted-by":"publisher","first-page":"4135","DOI":"10.1093\/nar\/gkp352","volume":"37","author":"H Makkonen","year":"2009","unstructured":"Makkonen, H., Kauhanen, M., Paakinaho, V., Jaaskelainen, T. & Palvimo, J. J. Long-range activation of FKBP51 transcription by the androgen receptor via distal intronic enhancers. Nucleic Acids Res 37, 4135\u20134148, 10.1093\/nar\/gkp352 (2009).","journal-title":"Nucleic Acids Res"},{"key":"BFsrep35354_CR28","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1002\/pros.21301","volume":"71","author":"A Aparicio","year":"2011","unstructured":"Aparicio, A. et al. Neuroendocrine prostate cancer xenografts with large-cell and small-cell features derived from a single patient\u2019s tumor: morphological, immunohistochemical, and gene expression profiles. Prostate 71, 846\u2013856, 10.1002\/pros.21301 (2011).","journal-title":"Prostate"},{"key":"BFsrep35354_CR29","doi-asserted-by":"publisher","first-page":"5194","DOI":"10.1158\/0008-5472.CAN-10-4374","volume":"71","author":"YC Lee","year":"2011","unstructured":"Lee, Y. C. et al. BMP4 promotes prostate tumor growth in bone through osteogenesis. Cancer Res 71, 5194\u20135203, 10.1158\/0008-5472.CAN-10-4374 (2011).","journal-title":"Cancer Res"},{"key":"BFsrep35354_CR30","doi-asserted-by":"publisher","first-page":"e51189","DOI":"10.1371\/journal.pone.0051189","volume":"7","author":"F Dayyani","year":"2012","unstructured":"Dayyani, F. et al. Combined Inhibition of IGF-1R\/IR and Src family kinases enhances antitumor effects in prostate cancer by decreasing activated survival pathways. PLoS One 7, e51189, 10.1371\/journal.pone.0051189 (2012).","journal-title":"PLoS One"},{"key":"BFsrep35354_CR31","doi-asserted-by":"publisher","first-page":"2697","DOI":"10.1172\/JCI33093","volume":"118","author":"ZG Li","year":"2008","unstructured":"Li, Z. G. et al. Androgen receptor-negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms. J Clin Invest 118, 2697\u20132710, 10.1172\/JCI33093 (2008).","journal-title":"J Clin Invest"},{"key":"BFsrep35354_CR32","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.jsbmb.2005.01.003","volume":"93","author":"V Luu-The","year":"2005","unstructured":"Luu-The, V., Pelletier, G. & Labrie, F. Quantitative appreciation of steroidogenic gene expression in mouse tissues: new roles for type 2 5alpha-reductase, 20alpha-hydroxysteroid dehydrogenase and estrogen sulfotransferase. J Steroid Biochem Mol Biol 93, 269\u2013276, 10.1016\/j.jsbmb.2005.01.003 (2005).","journal-title":"J Steroid Biochem Mol Biol"},{"key":"BFsrep35354_CR33","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1016\/0024-3205(92)90204-3","volume":"50","author":"WM van Weerden","year":"1992","unstructured":"van Weerden, W. M., Bierings, H. G., van Steenbrugge, G. J., de Jong, F. H. & Schroder, F. H. Adrenal glands of mouse and rat do not synthesize androgens. Life Sci 50, 857\u2013861 (1992).","journal-title":"Life Sci"},{"key":"BFsrep35354_CR34","doi-asserted-by":"publisher","first-page":"1086","DOI":"10.1210\/jcem.79.4.7962278","volume":"79","author":"A Belanger","year":"1994","unstructured":"Belanger, A. et al. Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80-year-old men. J Clin Endocrinol Metab 79, 1086\u20131090, 10.1210\/jcem.79.4.7962278 (1994).","journal-title":"J Clin Endocrinol Metab"},{"key":"BFsrep35354_CR35","doi-asserted-by":"publisher","first-page":"3951","DOI":"10.1210\/jcem.81.11.8923843","volume":"81","author":"EP Guazzo","year":"1996","unstructured":"Guazzo, E. P., Kirkpatrick, P. J., Goodyer, I. M., Shiers, H. M. & Herbert, J. Cortisol, dehydroepiandrosterone (DHEA), and DHEA sulfate in the cerebrospinal fluid of man: relation to blood levels and the effects of age. J Clin Endocrinol Metab 81, 3951\u20133960, 10.1210\/jcem.81.11.8923843 (1996).","journal-title":"J Clin Endocrinol Metab"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep35354.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep35354","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep35354.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T23:56:26Z","timestamp":1672876586000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep35354"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,10,17]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,12,16]]}},"alternative-id":["BFsrep35354"],"URL":"https:\/\/doi.org\/10.1038\/srep35354","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,10,17]]},"assertion":[{"value":"2 June 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 September 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 October 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"35354"}}