Reprogramming cell death: BCL2 family inhibition in hematological malignancies

The BCL2 family members play a central role in regulating programmed cell death (apoptosis) and arbitrating the cellular fate through an accurate balance between pro-apoptotic (BAX, BAK, and BH3-only proteins) and pro-survival (BCL2 and its closest homologues, BCLXL, BCLW and MCL-1) factors. Deregulation of BCL2 family proteins contributes to programmed cell death evasion, that is a hallmark of human cancers and it is often related to (chemo)therapy resistance. High BCL2 levels have been detected in most human lymphoid malignancies, not limited to follicular lymphoma (where the role of BCL2 overexpression is driven by the t[14;18] translocation) but also B-cell chronic lymphocytic leukemia (CLL) and multiple myeloma. For all these reasons, the opportunity to induce apoptosis by targeting BCL2 proteins is considered a potentially promising therapeutic approach in hematological malignancies. BCL2 family inhibition strategies currently explored in phase 1, 2 and 3 clinical trials are essentially two: (1) the use of antisense-based strategies to knockdown BCL2 or BCLXL expression (e.g. oblimersen) or (2) the use of synthetic BH3 mimetics i.e. small molecules binding to anti-apoptotic inhibitors thereby allowing the pro-apoptotic activity of BH3-only molecules (e.g. obatoclax, AT-101, ABT-737 and its derivatives ABT-263 and ABT-199). Several of these drugs demonstrated relevant clinical activity as single-agent or in combination therapy, with the most significant drawbacks in clinical use being represented by challenging pharmacokinetic profile (e.g. iv administration, high-levels of plasma proteins binding) and on-target side effects (e.g. gastrointestinal toxicity and thrombocytopenia). Further clinical development of the current compounds (e.g. ABT-199), showing high efficacy but devoid of the most threatening drug-related toxicities, is eagerly awaited. Hopefully, in the next future, BCL2 inhibitors (alone or in combination with immuno- and/or chemo-therapeutic agents) will represent target-specific drugs expanding our therapeutic armamentarium in the fight against hematologic malignancies.