John Petrini, Ph.D., Memorial Sloan Kettering Cancer Center, IDEAYA SAB Member
Synthetic Lethality and DNA Damage
Synthetic lethality (SL) is a concept first identified in the model genetic system Drosophila melanogaster (fruit fly) and recapitulated in yeast and other organisms. It was first suggested as a potential cancer treatment modality nearly 20 years ago (Hartwell et al 1997) and proof of concept for the approach now exists with the 2014 approval of the PARP inhibitor, Lynparza (olaparib), as an effective treatment for patients with BRCA 1/2 mutant ovarian cancer. Importantly, this biomarker driven approach to direct therapy to a “BRCA” subset of ovarian cancer patients has resulted in superior response rates and significant progression free survival. IDEAYA is prosecuting a novel set of DNA repair-based drug targets through a unique, tripartite approach that integrates 1) robustness and conservation of SL interactions across different organisms and in human tumor cells, 2) disease relevance of drug target and prevalent loss-of-function mutation in SL partner gene, and 3) small-molecule druggability. Another area of focus for IDEAYA will be to exploit the potential of modulating DNA repair with small molecules to augment response to immunotherapy.
The concept of stimulating the human immune system to kill tumor cells has been around since the work of Coley a century ago. Recent advances in immuno-oncology (IO), using an array of treatment modalities is transforming cancer therapy. IDEAYA’s IO programs are focusing on small-molecule druggable targets that function to cause an immune-suppressed, tumor-growth permissive microenvironment. Small-molecule agents targeting these key pathways are predicted to augment immune response directed at tumor cells as monotherapy but also in combination with other immune system targeting therapies to maximize therapeutic response.
The Tumor Microenvironment
Reference: Mellman, Coukas and Dranoff, Cancer Immunotherapy Comes of Ages, Nature 2011