Defining the impact of DNA repair variants on immune-based therapy of ovarian cancer at scale

Very few women with high-grade serous ovarian cancer (HGSOC) are successfully treated, and their lifespan after diagnosis is often months. We are working to increase success rates by identifying tools to improve existing treatments so they work better for patients. Treatments include PARP inhibitors (PARPi) and immune checkpoint blockade (ICB). Tumors have damaged DNA, and they fix it through a DNA repair pathway called homologous recombination (HR). The HR pathway, however, is defective or broken in about half of HGSOC cases. Specific effects of most individual HR gene mutations on tumor growth and treatment are unknown. To shed light on this issue, three research groups will integrate their expertise in DNA/genome stability (New York), HGSOC biology (Milan), and HGSOC-related immunotherapy (Chicago). Cutting-edge technologies will be applied to screen >22,000 HR gene mutations in a model system using cells from patients. This system will be used to identify specific mutations that affect HGSOC responses to PARPi and ICB. The clinical importance of our research will be defined by analyzing samples and data from a recent clinical trial on HGSOC patients treated with PARPi + ICB. Our goal is to define predictive, HR-related biomarkers that will help identify patients who are more likely to respond to PARPi and ICB. This information could help physicians decide what treatments are best for individual patients and increase success rates of HGSOC treatments.