Castration-resistant prostate cancer: locking up the molecular escape routes.
The understanding of the key role that androgens play on the normal and pathological physiology of the prostate guided the development of different therapies for the treatment of locally advanced or metastatic prostate cancer (PCa). These so-called androgen deprivation therapies include surgical or chemical castration, achieved by the administration of gonadotropin-releasing hormone analogs; inhibition of steroidogenic enzymes; and finally, blocking of the binding of androgens to their receptor (AR) by the use of antiandrogens. Despite an excellent initial response, in approximately 2 to 3 years, most of these patients will succumb to the castration resistant form of the disease. Remarkably, even in the presence of castration levels of circulating androgens, these tumors are still dependent on a functional AR, and several molecular mechanisms have been proposed to explain this phenomenon. These include: (1) gene amplification and increased expression of the AR mRNA and protein, (2) selection of mutations in the AR that confer broader ligand specificity, (3) changes in the ratios or expression between the AR and its coregulators, (4) increased expression of steroidogenic enzymes, and (5) up-regulation of cross-talk signal transduction pathways that can activate the AR in a ligand-independent manner. We will summarize how these molecular hypotheses are being tested in the clinic by the latest therapeutic modalities.
Attar
Ricardo M
RM
Ortho Biotech Oncology R&D/Centocor R&D, Radnor, PA 19087, USA. rattar1@its.jnj.com
Takimoto
Chris H
CH
Gottardis
Marco M
MM
D000726:Androgen Antagonists / Q000627:therapeutic use; D000728:Androgens / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008954:Models, Biological; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
C410798:AR protein, human; D000726:Androgen Antagonists; D000728:Androgens; D011944:Receptors, Androgen