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BCL-2 Antagonism to Target the Intrinsic Mitochondrial Pathway of Apoptosis
Christopher J Gibson1, Matthew S Davids2
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Abstract:
Despite significant improvements in treatment, cure rates for many cancers remain suboptimal. The rise of cytotoxic chemotherapy has led to curative therapy for a subset of cancers, though intrinsic treatment resistance is difficult to predict for individual patients. The recent wave of molecularly targeted therapies has focused on druggable-activating mutations, and is thus limited to specific subsets of patients. The lessons learned from these two disparate approaches suggest the need for therapies that borrow aspects of both, targeting biologic properties of cancer that are at once distinct from normal cells and yet common enough to make the drugs widely applicable across a range of cancer subtypes. The intrinsic mitochondrial pathway of apoptosis represents one such promising target for new therapies, and successfully targeting this pathway has the potential to alter the therapeutic landscape of therapy for a variety of cancers. Here, we discuss the biology of the intrinsic pathway of apoptosis, an assay known as BH3 profiling that can interrogate this pathway, early attempts to target BCL-2 clinically, and the recent promising results with the BCL-2 antagonist venetoclax (ABT-199) in clinical trials in hematologic malignancies. See all articles in this CCR Focus section, "Cell Death and Cancer Therapy."
Insights
Targeting the intrinsic mitochondrial apoptosis pathway offers a promising strategy for cancer therapy. BH3 profiling and BCL-2 inhibitors like venetoclax show potential for broad applicability across cancer types.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Cancer treatment cure rates remain suboptimal despite advances in chemotherapy and targeted therapies.
- Current therapies face challenges with intrinsic resistance and limited applicability to specific patient subsets.
- There is a need for broadly applicable cancer therapies targeting common cancer-specific vulnerabilities.
Purpose of the Study:
- To explore the intrinsic mitochondrial pathway of apoptosis as a therapeutic target in cancer.
- To discuss the utility of BH3 profiling in interrogating this pathway.
- To review clinical advancements in targeting BCL-2, including venetoclax.
Main Methods:
- Discussion of the biology of the intrinsic apoptosis pathway.
- Description of BH3 profiling as an assay for pathway interrogation.
- Review of clinical data for BCL-2 targeting agents.
Main Results:
- The intrinsic mitochondrial apoptosis pathway is a viable target for novel cancer therapies.
- BH3 profiling can effectively interrogate the apoptotic pathway.
- Venetoclax (ABT-199) has shown promising results in clinical trials for hematologic malignancies.
Conclusions:
- Targeting the intrinsic apoptosis pathway holds significant potential to improve cancer treatment outcomes.
- Venetoclax represents a successful example of targeting BCL-2 for cancer therapy.
- This approach may broaden therapeutic options across various cancer subtypes.
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