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Targeting of CYP17A1 Lyase by VT-464 Inhibits Adrenal and Intratumoral Androgen Biosynthesis and Tumor Growth of Castration Resistant Prostate Cancer
- Source :
- Scientific Reports
- Publication Year :
- 2016
- Publisher :
- Nature Publishing Group, 2016.
-
Abstract
- Cytochrome P450 17α-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 17α-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
- Subjects :
- Male
0301 basic medicine
medicine.medical_specialty
Hydrocortisone
Biopsy
Abiraterone Acetate
Dehydroepiandrosterone
Mice, SCID
Naphthalenes
Biology
urologic and male genital diseases
Article
Mass Spectrometry
Mice
03 medical and health sciences
Prostate cancer
chemistry.chemical_compound
Cell Line, Tumor
Internal medicine
medicine
Animals
Humans
Precision Medicine
Receptor
Multidisciplinary
Abiraterone acetate
Steroid 17-alpha-Hydroxylase
Triazoles
Lyase
medicine.disease
3. Good health
Androgen receptor
Prostatic Neoplasms, Castration-Resistant
030104 developmental biology
Endocrinology
chemistry
Receptors, Androgen
CYP17A1
Androgens
Prednisone
Signal transduction
Neoplasm Transplantation
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....274739c676d9370f5a704386b03a2a47
- Full Text :
- https://doi.org/10.1038/srep35354