Bcl-2 family of proteins as therapeutic targets in genitourinary neoplasms.
BACKGROUND
Overexpression of antiapoptotic B-cell lymphoma (Bcl-2) proteins confers the dysregulation of apoptosis and results in drug resistance in a variety of cancers, including those of the genitourinary tract. Inhibitors that target prosurvival Bcl-2 proteins are in preclinical and clinical development. The objective of this review is to assess the involvement of Bcl-2 proteins as well as the preclinical and clinical activity of Bcl-2 inhibitors under evaluation for genitourinary neoplasms.


METHODS
PubMed was used with both medical subject heading terms and free search to identify the relevant literature. Information on clinical trials was obtained using http://Clincaltrials.gov, EU Clinical Trials Register, and meeting abstracts of the American Society of Clinical Oncology.


RESULTS
To date, 2 Bcl-2 inhibitors have been evaluated in clinical trials for genitourinary tumors (oblimersen and AT-101 (R-(-)-gossypol)). Both agents demonstrated some success in early stages of development, but their clinical activity did not meet expectations. Preclinical studies are under way for other Bcl-2 inhibitors including ABT-737, HA14-1, and Bcl-2 homology 3 inhibitors.


CONCLUSIONS
Antiapoptotic Bcl-2 proteins are potential molecular targets in genitourinary cancers. Bcl-2 inhibitors might be effective as single agents or in combination with conventional therapies. However, the biology of the Bcl-2 family in genitourinary cancers remains poorly understood and robust preclinical studies are needed to inform clinical development. Such studies should aim to identify: (1) pharmacodynamic markers that could help guide patient selection for treatment with Bcl-2 inhibitors, and (2) optimal combinations of Bcl-2 inhibitors with other anticancer agents for future clinical investigation.
Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79416, USA.
Connor
C
Hall
Sarah M
SM
Troutman
Douglas K
DK
Price
William D
WD
Figg
Min H
MH
Kang
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000008:administration & dosage; D002986:Clinical Trials as Topic; D006072:Gossypol / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D058990:Molecular Targeted Therapy; D009596:Nitrophenols / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage; D013873:Thionucleotides / Q000008:administration & dosage; D014565:Urogenital Neoplasms / Q000188:drug therapy*
C501332:ABT-737; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D013873:Thionucleotides; C408162:oblimersen; D006072:Gossypol; C028178:gossypol acetic acid