RGD Reference Report - Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. - Rat Genome Database

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Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven.

Authors: Attard, G  Reid, AH  Yap, TA  Raynaud, F  Dowsett, M  Settatree, S  Barrett, M  Parker, C  Martins, V  Folkerd, E  Clark, J  Cooper, CS  Kaye, SB  Dearnaley, D  Lee, G  De Bono, JS 
Citation: Attard G, etal., J Clin Oncol. 2008 Oct 1;26(28):4563-71. Epub 2008 Jul 21.
RGD ID: 4846627
Pubmed: PMID:18645193   (View Abstract at PubMed)
DOI: DOI:10.1200/JCO.2007.15.9749   (Journal Full-text)

PURPOSE: Studies indicate that castration-resistant prostate cancer (CRPC) remains driven by ligand-dependent androgen receptor (AR) signaling. To evaluate this, a trial of abiraterone acetate-a potent, selective, small-molecule inhibitor of cytochrome P (CYP) 17, a key enzyme in androgen synthesis-was pursued. PATIENTS AND METHODS: Chemotherapy-naive men (n = 21) who had prostate cancer that was resistant to multiple hormonal therapies were treated in this phase I study of once-daily, continuous abiraterone acetate, which escalated through five doses (250 to 2,000 mg) in three-patient cohorts. RESULTS: Abiraterone acetate was well tolerated. The anticipated toxicities attributable to a syndrome of secondary mineralocorticoid excess-namely hypertension, hypokalemia, and lower-limb edema-were successfully managed with a mineralocorticoid receptor antagonist. Antitumor activity was observed at all doses; however, because of a plateau in pharmacodynamic effect, 1,000 mg was selected for cohort expansion (n = 9). Abiraterone acetate administration was associated with increased levels of adrenocorticotropic hormone and steroids upstream of CYP17 and with suppression of serum testosterone, downstream androgenic steroids, and estradiol in all patients. Declines in prostate-specific antigen >or= 30%, 50%, and 90% were observed in 14 (66%), 12 (57%), and 6 (29%) patients, respectively, and lasted between 69 to >or= 578 days. Radiologic regression, normalization of lactate dehydrogenase, and improved symptoms with a reduction in analgesic use were documented. CONCLUSION: CYP17 blockade by abiraterone acetate is safe and has significant antitumor activity in CRPC. These data confirm that CRPC commonly remains dependent on ligand-activated AR signaling.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
prostate cancer  IMP 4846627 RGD 
prostate cancer  ISOCYP17A1 (Homo sapiens)4846627; 4846627 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cyp17a1  (cytochrome P450, family 17, subfamily a, polypeptide 1)

Genes (Mus musculus)
Cyp17a1  (cytochrome P450, family 17, subfamily a, polypeptide 1)

Genes (Homo sapiens)
CYP17A1  (cytochrome P450 family 17 subfamily A member 1)


Additional Information