Selective Advantage of Apoptosis Defects
Apoptosis defects compliment protooncogene activation, as evidenced pro-proliferative genes (ex.Myc, E1a, Cyclin D1, etc.) which are normally counter-balanced by pro-apoptotic pathways. Defects in apoptosis permit survival of genetically unstable cells which are normally eradicated upon detection of defective DNA repair and chromosome segragation. It naturally follows that apoptosis defects facilitate metastisis by allowing epithelial cells to survive in suspension independent of ECM attachment. Apoptosis defects confer resistance to the immune system, since cytotoxic T cells (CTLs) and natural killer (NK) cells eradicate targets utilizzing in-tact apoptotic circuitry.Finally, apoptotic defects increase the threshold of the DDR required for cell death, thus confering chemoresistance or radioresistance.
Targeting the Interinsic (Mitochondiral) Apoptotic Pathway
Brief Review of Pathway
The intrinsic (a.k.a. stress-activated) apoptotic pathway can be initiated within the cell by transcriptional activation (ex. via p53 or E2F1 transcription factors) of genes encoding pro-apoptotic Bcl-2-related family members which congregate at the outer surface of the mitochondrial membrane to trigger depolarization (loss of normal voltage gradient), causing release of cytochrome C. Cytochrome C spills out into the cytosol to associate with Apaf-1 and form a functional seven-spoked apoptosome which activates initiator pro-caspase-9 to trigger the apoptotic caspase cascade. The open mitochondrial membrane channel also releases other pro-apoptotic proteins such as Smac/DIABLO which antagonize the inhibitors of apoptosis (IAPs) that normally bind and inactivate the caspases.
Intrinsic Pathway Therapeutics
Central regulators of the intrinsic pathway are pro- or anti- apoptotic Bcl-2 family members which eiyher suppress or promote changes in mitochondrial membrane permeability required for release of cytochrome C and other apoptotic proteins. Approximately 50% of all cancers are thought to overexpress antiapoptotic Bcl-2 or Bcl-XL to confer resistance to apoptotic stimuli, including most cytotoxic anti-cancer drugs..
Prior attempts to modulate expression of BCL-2 and BCl-XL have focused on druggable modulators of BCL-2 and BCL-XL expression, such as members of the steroid/retinoid superfamily of ligand-activated transcription factors. For example, in the mammary gland, expression of BCL-2 is estrogen-dependent. Anti-estrogens (ex. tamoxifen) inhibit endogenous BCL-2 expression in breast cancer cell lines, and promote sensitivity to cytotoxic anticancer drugs such as doxorubicin. Conversely, antisense BCL-2 prrevents estrogen-mediated apoptosis suppression. Thus utilization of anti-estrogens represent a viable approach to suppress expression of BCL-2 in ER-positive breast cancers. Furthermore, Bcl-2 or Bcl-XL expression can be down-regulated in specific types of cancer and leukemia cells by small molecule drugs that modulate activity of retinoic acid receptors (RAR), retinoid X receptors (RXR), PPARɣ, vitamin D receptors (VDR), and certain other members of the SRTF superfamily.
Nuclease-resistant (phosphorothioate) antisense oligonucleotodes targeting the BCL-2 mRNA have advanced to Phase III clinical trials for melanoma, myeloma, CLL, and AML, with Phase II underway for a variety of solid tumors.