TY - JOUR
T1 - Bcl-2 family of proteins as therapeutic targets in genitourinary neoplasms
AU - Hall, Connor
AU - Troutman, Sarah M.
AU - Price, Douglas K.
AU - Figg, William D.
AU - Kang, Min H.
PY - 2013/3
Y1 - 2013/3
N2 - Introduction: 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. Materials and 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. Conclusion: 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.
AB - Introduction: 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. Materials and 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. Conclusion: 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.
KW - Apoptosis
KW - Bcl-2 inhibitors
UR - http://www.scopus.com/inward/record.url?scp=84874547247&partnerID=8YFLogxK
U2 - 10.1016/j.clgc.2012.09.002
DO - 10.1016/j.clgc.2012.09.002
M3 - Review article
C2 - 23083798
AN - SCOPUS:84874547247
SN - 1558-7673
VL - 11
SP - 10
EP - 19
JO - Clinical Genitourinary Cancer
JF - Clinical Genitourinary Cancer
IS - 1
ER -