Mechanism of Action

Bcl-2 blocks apoptosis—and chemotherapy effectiveness

Bcl-2 protein is a key inhibitor of apoptotic cell death.  This central role in biology, coupled with increased expression in many solid tumors and hematologic cancers, makes Bcl-2 a critical target in cancer therapy.

• Apoptosis Pathways
• MOA
• Link to Cancer

• Bcl-2 and related protein family members play a pivotal role in the normal process of cell death (known as apoptosis). Apoptosis typically occurs after the cell is damaged by an external shock.  (In the case of a cancer cell, the shock might be in the form of chemotherapy or an immunotherapy-based injury).  The regulation of this process — namely, the decision to initiate the process of cell death — is routed through a pathway that is centrally controlled by Bcl-2 protein family members, as depicted in the accompanying video and in the figure below.

  Click the image below to enlarge

  

  Apoptotic signal pathways and regulators of apoptosis (Adapted from Johnstone et al. Cell. 2002)

• Bcl-2 is normally located between the bilaminar membranes of the mitochondrion.  Bcl-2 is believed to prevent the release of a substance known as cytochrome C from inside the mitochondria, which would otherwise trigger apoptosis by activating enzymes known as caspases.

  Most types of chemotherapy seek to induce cellular damage to induce apoptosis.  However, the presence of excess Bcl-2 blocks the release of cytochrome C that would otherwise be triggered by chemotherapy.  Thus, excess Bcl-2 appears to be a fundamental cause of the resistance of cancer cells to standard anticancer therapy.  Genasense^® has been designed to inhibit the production of Bcl-2, thereby restoring the potential for tumor cells to be killed with current cancer therapies.

  By reducing Bcl-2, Genasense may unblock the mitochondrial release of cytochrome C when appropriately triggered by chemotherapy; thus, initiating the cascade of caspase activation. The process is outlined in the image below.

   

• Bcl-2 is highly expressed in many types of cancer. The figure below shows results from a survey of medical literature on the proportion of patients with various types of cancer whose tumor cells at the time of initial diagnosis over-express Bcl-2 relative to a relevant normal cellular counterpart. Bcl-2 appears to be a major contributor to both inherent and acquired resistance to current anticancer treatments.

   

  

  Preclinical Evidence That Genasense Decreases Bcl-2 Protein

  In an initial clinical study, the expression of Bcl-2 protein in tumor tissue was evaluated in patients with advanced melanoma who were treated with the combination of Genasense^® plus  dacarbazine.  These data showed that systemic administration of Genasense was associated with down-regulation of Bcl-2 protein in tumor tissue from most patients. Results from this preclinical trial were published in the Lancet .

   

  Serial Biopsies
  Bcl-2
  Actin
  % of Baseline	100% Day 0	30% Day 5

   

  Reference: Jansen B, et al.: Chemosensitisation of malignant melanoma by BCL2 antisense therapy. Lancet 356(9243):1728-33, 2000