Deregulation of apoptosis (or programmed cell death) is a hallmark of cancer cells. Apoptosis is classically triggered by two upstream pathways, named the intrinsic and extrinsic pathways, the final result being activation of several cysteine proteases called caspases and induction of an apoptotic cell phenotype. The extrinsic pathway of apoptosis is triggered mainly by death receptors and their ligands, while the intrinsic pathway (also named the mitochondrial pathway) is activated by DNA damage and defective cell cycle and triggered by Bcl-2 family members. Inducing apoptosis in cancer cells represents a novel and promising area of discovery and research. Targeting elements from the extrinsic or intrinsic pathway may have either a direct proapoptotic effect or sensitize cancer cells to other cytotoxics. Several drugs are being developed to target death receptors, including monoclonal antibodies to the TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) receptors. Mapatumumab is a fully human monoclonal antibody to TRAIL-R1 currently undergoing phase II clinical development as a single agent and in combination with chemotherapies. Combination studies with other therapeutic options such as targeted therapies are either ongoing or planned. Preclinical and clinical studies with mapatumumab demonstrated an acceptable toxicity profile, as well as encouraging antitumor activity.
ASJC Scopus subject areas
- Pharmacology (medical)