Clinical appraisal of abiraterone in the treatment of metastatic prostatic cancer: patient considerations, novel opportunities, and future directions

被引:12
作者
Bedoya, Diego J. [1 ]
Mitsiades, Nicholas [2 ,3 ]
机构
[1] Clearview Canc Inst, Huntsville, AL USA
[2] Baylor Coll Med, Dept Med, Houston, TX 77030 USA
[3] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
来源
ONCOTARGETS AND THERAPY | 2013年 / 6卷
关键词
androgen synthesis; testosterone; dihydrotestosterone; CYP17; AKR1C3; MDV3100 (enzalutamide); ANDROGEN RECEPTOR TRANSACTIVATION; STEROIDOGENIC ENZYMES; DIHYDROTESTOSTERONE LEVELS; ANTIANDROGEN WITHDRAWAL; CYP17A1; INHIBITION; INCREASED SURVIVAL; PLUS PREDNISONE; CASTRATION; EXPRESSION; ACETATE;
D O I
10.2147/OTT.S24941
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
While androgen-deprivation therapy can induce dramatic clinical responses in advanced and metastatic prostate cancer, refractory disease (castration-resistant prostate cancer [CRPC]) eventually emerges. In recent years, several studies have demonstrated the importance of residual intratumoral androgens in maintaining androgen receptor (AR) transcriptional activity in CRPC. The cytochrome P450 enzyme CYP17 is an obligatory step in androgen synthesis, and therefore a critical therapeutic target in CRPC. Abiraterone acetate is a selective, irreversible inhibitor of CYP17 and can suppress adrenal synthesis of androgen precursors, and possibly in situ steroidogenesis in the tumor microenvironment. In a phase III multicenter study, abiraterone in combination with prednisone improved median overall survival of men with docetaxel-refractory CRPC by 3.9 months compared to placebo plus prednisone, and also resulted in higher objective prostate-specific antigen and radiographic response rates. The study led to the FDA approval in April 2011 of abiraterone for treatment of chemotherapy-refractory CRPC patients, validating steroidogenesis and the AR axis in general as therapeutic targets in CRPC. The FDA indication for abiraterone was expanded to all CRPCs in December 2012, while evaluation in even earlier disease states is ongoing. We propose a comprehensive AR axis-targeting approach via simultaneous, frontline enzymatic blockade of several steroidogenic enzymes (eg, CYP17 and AKR1C3) in combination with gonadotropin-releasing hormone analogs and potent, second-generation AR antagonists (eg, enzalutamide) in order to improve outcomes in patients with prostate cancer.
引用
收藏
页码:9 / 18
页数:10
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共 80 条
[1]   Activation of cAMP-dependent protein kinase increases the protein level of steroidogenic factor-1 [J].
AEsoy, R ;
Mellgren, G ;
Morohashi, KI ;
Lund, J .
ENDOCRINOLOGY, 2002, 143 (01) :295-303
[2]   Src kinase potentiates androgen receptor transactivation function and invasion of androgen-independent prostate cancer C4-2 cells [J].
Asim, M. ;
Siddiqui, I. A. ;
Hafeez, B. B. ;
Baniahmad, A. ;
Mukhtar, H. .
ONCOGENE, 2008, 27 (25) :3596-3604
[3]   Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer [J].
Attard, G ;
Belldegrun, AS ;
de Bono, JS .
BJU INTERNATIONAL, 2005, 96 (09) :1241-1246
[4]   Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven [J].
Attard, Gerhardt ;
Reid, Alison H. M. ;
Yap, Timothy A. ;
Raynaud, Florence ;
Dowsett, Mitch ;
Settatree, Sarah ;
Barrett, Mary ;
Parker, Christopher ;
Martins, Vanessa ;
Folkerd, Elizabeth ;
Clark, Jeremy ;
Cooper, Colin S. ;
Kaye, Stan B. ;
Dearnaley, David ;
Lee, Gloria ;
de Bono, Johann S. .
JOURNAL OF CLINICAL ONCOLOGY, 2008, 26 (28) :4563-4571
[5]   Clinical and Biochemical Consequences of CYP17A1 Inhibition with Abiraterone Given with and without Exogenous Glucocorticoids in Castrate Men with Advanced Prostate Cancer [J].
Attard, Gerhardt ;
Reid, Alison H. M. ;
Auchus, Richard J. ;
Hughes, Beverly A. ;
Cassidy, Amy Mulick ;
Thompson, Emilda ;
Oommen, Nikhil Babu ;
Folkerd, Elizabeth ;
Dowsett, Mitch ;
Arlt, Wiebke ;
de Bono, Johann S. .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2012, 97 (02) :507-516
[6]   Selective Inhibition of CYP17 With Abiraterone Acetate Is Highly Active in the Treatment of Castration-Resistant Prostate Cancer [J].
Attard, Gerhardt ;
Reid, Alison H. M. ;
A'Hern, Roger ;
Parker, Christopher ;
Oommen, Nikhil Babu ;
Folkerd, Elizabeth ;
Messiou, Christina ;
Molife, L. Rhoda ;
Maier, Gal ;
Thompson, Emilda ;
Olmos, David ;
Sinha, Rajesh ;
Lee, Gloria ;
Dowsett, Mitch ;
Kaye, Stan B. ;
Dearnaley, David ;
Kheoh, Thian ;
Molina, Arturo ;
de Bono, Johann S. .
JOURNAL OF CLINICAL ONCOLOGY, 2009, 27 (23) :3742-3748
[7]   Intratumoral De Novo Steroid Synthesis Activates Androgen Receptor in Castration-Resistant Prostate Cancer and Is Upregulated by Treatment with CYP17A1 Inhibitors [J].
Cai, Changmeng ;
Chen, Sen ;
Ng, Patrick ;
Bubley, Glenn J. ;
Nelson, Peter S. ;
Mostaghel, Elahe A. ;
Marck, Brett ;
Matsumoto, Alvin M. ;
Simon, Nicholas I. ;
Wang, Hongyun ;
Chen, Shaoyong ;
Balk, Steven P. .
CANCER RESEARCH, 2011, 71 (20) :6503-6513
[8]   Molecular determinants of resistance to antiandrogen therapy [J].
Chen, CD ;
Welsbie, DS ;
Tran, C ;
Baek, SH ;
Chen, R ;
Vessella, R ;
Rosenfeld, MG ;
Sawyers, CL .
NATURE MEDICINE, 2004, 10 (01) :33-39
[9]   Targeting the androgen receptor pathway in prostate cancer [J].
Chen, Yu ;
Sawyers, Charles L. ;
Scher, Howard I. .
CURRENT OPINION IN PHARMACOLOGY, 2008, 8 (04) :440-448
[10]   Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target [J].
Chen, Yu ;
Clegg, Nicola J. ;
Scher, Howard I. .
LANCET ONCOLOGY, 2009, 10 (10) :981-991