Bcl-2 family of proteins as therapeutic targets in genitourinary neoplasms

Abstract

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.

Figure 1

Induction of the Caspase Cascade and Initiation of Apoptosis via the Extrinsic and Intrinsic Apoptotic Pathways. The Extrinsic Pathway of the Caspase Cascade is Mediated Independently of the Mitochondria. It is Activated by Death Receptors, Fas and Tumor-Necrosis Factor-Related Ligand (TRAIL), Which Initiate Caspase-8 in a Death-Signaling Complex. This Complex Subsequently Activates the Effector Caspase Cascade. In the Intrinsic Pathway, Apoptotic Stimuli Trigger the Release of Cytochrome c (cyt c), which Forms a Complex with Caspase 9 and Apoptosis Protease-Activating Factor (Apaf-1). This Apoptotic Complex goes on to Activate the Effector Caspase Cascade. The Signals to Release cyt c from the Mitochondria is Suppressed by the Anti-Apoptotic Bcl-2 Homology 1 to 4 (BH1 −4) Proteins and Incited by the Proapoptotic BH1 −3 Proteins

Figure 2

B-Cell Lymphoma (Bcl-2) Inhibitors in Clinical and Preclinical Development for Genitourinary Cancers. There are Currently 2 Classes of Bcl-2 Inhibitors in Clinical and Preclinical Development for Genitourinary Cancers: (A) Antisense Oligonucleotides (ASO) and (B) Small Molecule BH3 Mimetics. The ASO, Oblimersen Sodium, (1) is in Phase ll/Phase III Clinical Trials in Prostate Cancer and Renal Cell Carcinoma and Specifically Hybridizes to the First 6 Codons of the Open Reading Frame of bcl-2 mRNA. (2) Oblimersen Promotes the Recruitment of Endogenous RNase H to Mediate bcl-2 mRNA Degradation, (3) Thereby Reducing Bcl-2 Protein Synthesis and Expression (4) and is Able to Recycle and Repeat the Process. (5) BH3 Mimetics Bind to the Hydrophobic BH3 Binding Domain of Specific Anti-Apoptotic Bcl-2 Family Members and Disrupt Their Ability to Oppose Apoptosis. BH3I-2 (Preclinical; Prostate Cancer) Targets Bcl-2. HA14–1 (Preclinical; Prostate Cancer) Targets Bcl-2. ABT-737 (Preclinical; Prostate Cancer, Renal Cell Carcinoma, Transitional Cell Carcinoma of Bladder) and Apogossypolone (Preclinical; Prostate Cancer) Target Bcl-xL, Bcl-2, and Bcl-w. AT-101 (Phase II; Prostate Cancer, Renal Cell Carcinoma, Transitional Cell Carcinoma of Bladder) and GX15–070 (not in Development in Genitourinary Cancers) Target Bcl-xL, Bcl-2, Bcl-w, and Mcl-1. Parenthesis Denotes Furthest Stage of Development for Genitourinary Cancers