The DDR Pathway helps to control cell health. The DDR pathway is critical in repairing DNA damage in healthy cells that would otherwise cause mutations or cell death. When the DDR pathway is altered or unable to repair this damage, mutated cells can lose important instructions that normally prevent them from growing out of control. Cells with unresolved DDR defects can become cancerous. Cancerous cells with DDR defects may be more resistant to standard chemotherapies and radiation.
When a gene in the DDR pathway is damaged or fails, related genes compensate for its loss of function. Aprea’s approach is to inhibit compensatory genes, thereby specifically killing cancer cells with mutations in the DDR pathway. This approach is called synthetic lethality. Using synthetic lethality, Aprea’s drugs selectively kill cancer cells while minimizing the effect on normal, unmutated cells, decreasing the toxicity normally associated with cancer treatment.
Aprea Therapeutic’s molecules selectively target cancer cells in much the same way that commercially successful poly-ADP ribose polymerase (PARP) inhibitors target cancer cells with mutations in the BRCA genes. The difference is that our small molecule therapeutics selectively target cancer cells with faulty DDR pathways and compensatory gene functionality to potentially eliminate their growth.
Over a decade ago, our team was the first to recognize and report the DDR-related highly selective compounds can result in a high therapeutic index, which may lead to potentially fewer side effects for cancer patients. For over a decade, our team has applied its collective expertise to identify cancer-specific vulnerabilities that can be targeted by a synthetic lethality-based approach. Our small molecule inhibitors selectively bind to ATR and WEE1 genes–master regulators of the DNA-damage response– producing a potential preferred therapeutic index of increased efficacy and reduced toxicity for cancer patients with unmet medical needs.