Clement Chung1. 1. Lyndon B. Johnson General Hospital, Houston, TX clement_t_chung@yahoo.com.
Abstract
PURPOSE: The relevance of apoptosis to cancer development and pharmacologic agents that target this pathway in selected malignancies are described. SUMMARY: Apoptosis is a tightly regulated biological process mediated by both proapoptotic (i.e., prodeath) and antiapoptotic (i.e., prosurvival) proteins. While apoptosis represents a well-established effector mechanism induced by conventional chemotherapy in many malignancies, the development of apoptosis-based targeted therapy is relatively new. The pharmacologic restoration of apoptotic functions, either by blocking the action of antiapoptotic proteins/regulators (e.g., through investigational therapies such as inhibitors of apoptosis proteins, SMAC [second mitochondria-derived activator of caspases] mimetics, MDM2 [murine double minute 2] antagonists) or by inducing apoptosis (e.g., through investigational agonistic monoclonal antibodies or fusion proteins), holds robust potential for cancer pharmacotherapy. Notably, BH domain 3 (BH3) mimetics, a new class of small molecules that block the action antiapoptotic proteins, are touted a success for apoptosis-based targeted therapy. Venetoclax, a synthetic peptide that belongs to this class of BH3 mimetics, is currently approved by the Food and Drug Administration for the treatment of relapsed/refractory chronic lymphocytic leukemia in patients with 17p deletion as a single agent. This agent has been increasingly used either alone or as part of combination therapy for diverse hematologic malignancies in clinical trials. CONCLUSION: Advances in the understanding of molecular mechanisms of apoptosis have given rise to more-refined targeted therapies for diverse malignancies, with the goal to improve survival outcome while sparing treatment-related toxicities.
PURPOSE: The relevance of apoptosis to cancer development and pharmacologic agents that target this pathway in selected malignancies are described. SUMMARY: Apoptosis is a tightly regulated biological process mediated by both proapoptotic (i.e., prodeath) and antiapoptotic (i.e., prosurvival) proteins. While apoptosis represents a well-established effector mechanism induced by conventional chemotherapy in many malignancies, the development of apoptosis-based targeted therapy is relatively new. The pharmacologic restoration of apoptotic functions, either by blocking the action of antiapoptotic proteins/regulators (e.g., through investigational therapies such as inhibitors of apoptosis proteins, SMAC [second mitochondria-derived activator of caspases] mimetics, MDM2 [murine double minute 2] antagonists) or by inducing apoptosis (e.g., through investigational agonistic monoclonal antibodies or fusion proteins), holds robust potential for cancer pharmacotherapy. Notably, BH domain 3 (BH3) mimetics, a new class of small molecules that block the action antiapoptotic proteins, are touted a success for apoptosis-based targeted therapy. Venetoclax, a synthetic peptide that belongs to this class of BH3 mimetics, is currently approved by the Food and Drug Administration for the treatment of relapsed/refractory chronic lymphocytic leukemia in patients with 17p deletion as a single agent. This agent has been increasingly used either alone or as part of combination therapy for diverse hematologic malignancies in clinical trials. CONCLUSION: Advances in the understanding of molecular mechanisms of apoptosis have given rise to more-refined targeted therapies for diverse malignancies, with the goal to improve survival outcome while sparing treatment-related toxicities.