New agents and strategies for the hormonal treatment of castration-resistant prostate cancer.
BACKGROUND
Hormonal therapy with medical or surgical castration is the mainstay of systemic therapy for advanced prostate cancer. Depletion of gonadal testosterone in circulation is typically initially effective, although responses are transient and metastatic disease progresses as castration-resistant prostate cancer (CRPC).


METHODS
CRPC is accompanied by a gain of function in the androgen receptor (AR), which may occur at the level of AR itself or through intratumoral repletion of androgens that in turn stimulate AR. Investigational drugs in clinical trials have promising activity in CRPC. Abiraterone acetate is a CYP17A1 inhibitor that blocks the synthesis of adrenal androgens. MDV3100 is a nonsteroidal AR antagonist with a greater binding affinity than other AR antagonists currently in clinical use. Insights into the mechanisms of intratumoral steroidogenesis in CRPC have defined other potential targets. Metabolism from DHEA to testosterone and dihydrotestosterone requires 3-hydroxyl oxidation and Delta(5) isomerization to Delta(4) by 3beta-hydroxysteroid dehydrogenase (3betaHSD) and 17-keto reduction by 17beta-hydroxysteroid dehydrogenase (17betaHSD)-3 or -5. AR activation in CRPC by intratumoral steroids requires these enzymatic steps. Investigation into specific inhibitors of 3betaHSD and 17betaHSD are required to determine their efficacy and potential roles in the treatment of CPRC.


RESULTS
Readers will gain an understanding of the biology of CRPC, new investigational hormonal agents and novel approaches to the treatment of CRPC.


CONCLUSIONS
Intratumoral androgens drive CRPC progression. New investigational hormonal agents that inhibit intratumoral androgens are highly active in the treatment of CRPC. Alternative strategies hold the promise for the development of other agents with novel mechanisms of action.
Sharifi
Nima
N
Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8852, USA. nima.sharifi@utsouthwestern.edu
D000726:Androgen Antagonists / Q000627:therapeutic use*; D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D016896:Treatment Outcome
C410798:AR protein, human; D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D011944:Receptors, Androgen