Article

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

Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom.
Journal of Clinical Oncology (impact factor: 18.37). 10/2008; 26(28):4563-71. DOI:10.1200/JCO.2007.15.9749 pp.4563-71
Source: PubMed

ABSTRACT 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.
Chemotherapy-naïve 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.
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.
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.

0 0
 · 
0 Bookmarks
 · 
29 Views
  • Source
    Article: Open-label, phase I, pharmacokinetic studies of abiraterone acetate in healthy men.
    M Acharya, A Bernard, M Gonzalez, J Jiao, R De Vries, N Tran
    [show abstract] [hide abstract]
    ABSTRACT: To evaluate pharmacokinetics, safety, and tolerability of abiraterone acetate (AA) in healthy men. Two phase I studies (dose-escalation study and dose-proportionality study) were conducted in healthy men aged 18-55 years. All subjects received 4 consecutive single doses of AA (250, 500, 750 and 1,000 mg). The dose-escalation study subjects (N = 33) received AA doses in a sequential manner, starting with the lowest dose. The dose-proportionality study subjects (N = 32) were randomly allocated (1:1:1:1) to receive each of the 4 doses in a four-way crossover design. A dose-related increase in abiraterone exposure was observed in both studies. Over the evaluated dose range, the mean abiraterone maximum plasma concentrations increased from 26 to 112 ng/mL in dose-escalation study and from 40 to 125 ng/mL in dose-proportionality study; the mean area under the plasma concentration-time curve from 0 to the last measurable plasma concentration increased from 155 to 610 ng.h/mL in dose-escalation study, and from 195 to 607 ng.h/mL in dose-proportionality study. In the dose-proportionality study, abiraterone exposure was dose proportional between 1,000 and 750 mg doses; however, the exposure was slightly greater than dose proportional when exposures at 500 and 250 mg doses were compared with the exposure at 1,000 mg. Single doses of AA were well tolerated in healthy men, and safety profile was consistent with its known toxicities in CRPC patients. Systemic exposure to abiraterone increased with increasing doses of AA (250-1,000 mg) in healthy men; AA was well tolerated in this population.
    Cancer Chemotherapy and Pharmacology 04/2012; 69(6):1583-90. · 2.83 Impact Factor
  • Source
    Chapter: Cell Biology of Prostate Cancer and Molecular Targets
    Martin E. Gleave, Michael E. Cox, Yuzhuo Wang
    [show abstract] [hide abstract]
    ABSTRACT: While not appreciated at the time, the Nobel Prize-winning work of Huggins and Hodges in the 1940s illustrated the androgen dependence of prostate cancer and credentialized the first “targeted” (in this case, the androgen receptor) anticancer therapy. Androgen deprivation therapy induces long-term remission in most patients, but development of castration-resistant prostate cancer (CRPC) is inevitable. Most treatments for CRPC have been approved for symptomatic benefit, with only docetaxel shown to improve overall survival. Mechanisms underlying shift to castrate resistance have been attributed to a complex interplay of clonal selection, reactivation of AR axis despite castrate levels of serum T, adaptive upregulation of antiapoptotic and survival gene networks, stress-induced cytoprotective chaperones, and alternative growth factor pathways. CRPC tumors develop compensatory mechanisms during androgen deprivation, tailored to the synthesis of intratumoral androgens, which along with ligand-independent mechanisms involving cofactors or growth factor pathways, cooperatively trigger AR activation and thus disease progression. Over the last few years, numerous gene targets involved with CRPC that regulate apoptosis, proliferation, angiogenesis, cell signaling, and tumor-bone stromal interactions have been identified, and many novel compounds have entered clinical trials either as single agents or in combination with cytotoxic chemotherapy. In this review, several genes and pathways involved in CRPC progression will be reviewed, with particular emphasis on preclinically credentialized genes and pathways that are currently the targets of novel inhibitors in later stages of clinical development. These include the AR axis, molecular chaperones, tumor vasculature, bone stroma, and signal transduction pathways such as those triggered by IGF-1 and IL-6. KeywordsCastration-resistant prostate cancer-Androgen receptor-Clusterin-Hsp27-IGF-1
    09/2010: pages 1-24;
  • Source
    Article: Correction:Image guided dose escalated prostate radiotherapy: still room to improve.
    Jarad M Martin, Andrew Bayley, Robert Bristow, Peter Chung, Mary Gospodarowicz, Cynthia Menard, Michael Milosevic, Tara Rosewall, Padraig R Warde, Charles N Catton
    [show abstract] [hide abstract]
    ABSTRACT: ABSTRACT: We regret to report that a proofreading error caused an incorrect legend and description of the contents of table 6 to appear in our original publication of this work. The correct description of table 6 is: Univariate analysis of prognostic factors for 5-year nadir + 2 biochemical outcome for men presenting with intermediate risk factors.
    Radiation Oncology 12/2009; 4(1):65. · 2.32 Impact Factor

Show more

Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

Abiraterone acetate
 
Abiraterone acetate administration
 
abiraterone acetate-a potent
 
adrenocorticotropic hormone
 
androgen synthesis-was
 
anticipated toxicities attributable
 
castration-resistant prostate cancer
 
continuous abiraterone acetate
 
CYP17 blockade
 
cytochrome P
 
downstream androgenic steroids
 
ligand-dependent androgen receptor
 
mineralocorticoid receptor antagonist
 
multiple hormonal therapies
 
pharmacodynamic effect
 
secondary mineralocorticoid excess-namely hypertension
 
significant antitumor activity
 
steroids upstream
 
suppression
 
three-patient cohorts
 

Gerhardt Attard