Therapeutic Potential¹

• A feature that makes a TAA ideal for immunotherapy is the dependency of the malignant cells on the expression of the TAA.
• Targeting TAAs that drive the proliferation of the malignant clone will not only contribute to the reduction of the disease burden, but may also eliminate the underlying malignant clone/stem cell that must ultimately be eradicated for achieving cure.

Tumor Dependency:

The tumor dependency approach has produced new targeted therapies that may address one or more of the biological hallmarks of cancer that tumors exploit to proliferate, such as, resisting cell death (avoiding apoptosis) sustaining proliferative signaling, evading growth suppressors, and enabling replicative immortality.² The ability of tumor cell populations to expand in number is determined not only by the rate of cell proliferation (cell replication), but also by the rate of cell attrition (cell death):²

• Apoptosis, or programmed cell death, represents a major source of cell attrition.²
  • Sensors (intrinsic or extrinsic) are responsible for monitoring the extracellular and intracellular environment for conditions of normality or abnormality that influence whether a cell should live or die; these sentinels include cell surface receptors that bind survival or death factors.²
  • Effector enzymes (caspases) are regulated by the sensors and ultimately carry out the execution of the death program through selective destruction of subcellular structures and organelles and of the genome.²
  • The BCL-2 family of proteins in the intrinsic apoptosis pathway are “sensors” or “regulators” that control cell death primarily by direct binding interactions that regulate mitochondrial outer membrane permeabilization (MOMP), leading to the irreversible release of cytochrome C, subsequent caspase (“effectors”) activation, and the resulting apoptosis.³

Therapeutic Potential

• Acquired resistance to apoptosis is a hallmark of most, if not all, types of cancer.²
  • In cancer, apoptosis evasion through dysregulation of specific BCL-2 family genes is a recurring event.⁴
  • Dysregulation of the apoptotic pathways can not only promote tumorigenesis, but can also render cancer cells resistant to conventional anti cancer agents because, chemotherapy- and radiotherapy-induced killing of cancer cells is mainly mediated through activation of apoptosis.⁵
• Overexpression of anti-apoptotic BCL-2 family proteins (BCL-2, BCL-XL, BFL-1/A1, BCL-W and MCL-1) disrupts the dynamic balance of anti- and pro-apoptotic proteins, which may promote cancer cell survival.^5,6
  • The overexpression of these proteins is seen in a wide variety of hematologic malignancies and solid tumors.^5,7
  • The heterogeneity among tumors, even of the same type, necessitates a continued effort to further investigate mechanisms of apoptosis dysregulation in distinct cancer cell types.⁵
• Strategies to inhibit anti-apoptotic BCL-2 proteins include reducing protein expression by targeting the corresponding mRNA with an antisense oligonucleotide compound as well as blocking anti-apoptotic activity by targeting at the protein level.^5,6
  • There is interest in developing drugs that mimic the action of the BH3 domain by binding to one or more of the BCL-2-like proteins and triggering the apoptotic program.⁶