Novel molecular targets for the therapy of castration-resistant prostate cancer.
BACKGROUND
Improved understanding of mechanisms underlying metastatic castration-resistant prostate cancer (mCRPC) progression has led to the recognition of multiple molecular targets and advances in the therapeutic landscape. The addition of abiraterone acetate, sipuleucel-T, cabazitaxel, and denosumab to the therapeutic armamentarium and the impending addition of MDV-3100 and radium-223 underscore the importance of androgen pathway inhibition, immunotherapy, tubulin antagonism, and pathophysiology of bone metastasis.


OBJECTIVE
Review the next generation of molecular targets in mCRPC.


METHODS
Medline databases were searched for >100 original articles published as of October 18, 2011, with the search terms metastatic castration-resistant prostate cancer, targeted therapy, biologic agents, and immunotherapy. Proceedings from the last 5 yr of conferences of the American Society of Clinical Oncology, American Urological Association, European Society of Medical Oncology, and the European Association of Urology were also searched. We included novel and promising drugs that have reached clinical trial evaluation.


RESULTS
The major findings were addressed in an evidence-based fashion. Prospective trials and important preclinical data were analyzed.


CONCLUSIONS
mCRPC is a disease with multiple molecular drivers. Molecular pathways being targeted in ongoing phase 3 trials are androgen signaling (MDV3100, TAK700), immunoregulatory pathways (ipilimumab, Prostvac-VF-TRICOM), Src (dasatinib), Met (cabozantinib), clusterin (custirsen), and angiogenesis (aflibercept, tasquinimod). The strides made in identifying multiple other novel molecular targets offer potential opportunities for further improving outcomes.
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Neeraj
N
Agarwal
Guru
G
Sonpavde
Cora N
CN
Sternberg
D000069501:Abiraterone Acetate; D000730:Androstadienes / Q000627:therapeutic use; D000813:Anilides / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D019496:Cancer Vaccines / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy* / Q000556:secondary / Q000601:surgery; D017326:Clinical Trials, Phase III as Topic; D051152:Clusterin / Q000627:therapeutic use; D000069439:Dasatinib; D000069448:Denosumab; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D009570:Nitriles; D009919:Orchiectomy; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D011725:Pyridines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use; D015363:Quinolones; D011883:Radium / Q000627:therapeutic use; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D043823:Taxoids / Q000627:therapeutic use; D013844:Thiazoles / Q000627:therapeutic use; D014020:Tissue Extracts / Q000627:therapeutic use; D016896:Treatment Outcome; D014614:Vaccines, Synthetic / Q000627:therapeutic use
D000730:Androstadienes; D000813:Anilides; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001549:Benzamides; D019496:Cancer Vaccines; D051152:Clusterin; D000074324:Ipilimumab; D009570:Nitriles; D011725:Pyridines; D011743:Pyrimidines; D011804:Quinolines; D015363:Quinolones; D011993:Recombinant Fusion Proteins; D043823:Taxoids; D013844:Thiazoles; D014020:Tissue Extracts; D014614:Vaccines, Synthetic; C439566:rV-Tricom; C533178:aflibercept; C558660:cabozantinib; D010669:Phenylthiohydantoin; D000069448:Denosumab; C552428:cabazitaxel; C516109:tasquinimod; C511774:sipuleucel-T; C540278:enzalutamide; D040262:Receptors, Vascular Endothelial Growth Factor; D000069501:Abiraterone Acetate; D000069439:Dasatinib; D011883:Radium