DNA Damage as a Predictive Biomarker for Immunotherapy Response in Ovarian Cancer
Abstract
Ovarian cancer is incredibly challenging to treat because of a high recurrence rate even among individuals who enter remission after first-line treatment. Recurrent tumors develop resistance to therapy and eventually lead to patient death. There is a critical need to improve the effectiveness of first-line chemotherapies and to improve the selection of subsequent therapies for recurrent patients. Immunotherapies offer new strategies for the treatment of ovarian cancer, but we currently do not have good indicators for the use of immunotherapies in ovarian cancer patients. Several reports have link changes in DNA repair pathways with sensitivity to immunotherapies, but biomarkers for changes in DNA repair have not been developed for immunotherapy use. We have developed a novel strategy for measure DNA damage in tumor tissues that can report on the proficiency or deficiency in DNA repair pathways. We propose that measuring DNA damage levels and, therefore, DNA repair efficiency in ovarian tumors, will offer new biomarkers to improve patient stratification for immunotherapies. We will test this hypothesis in parallel with an ongoing clinical trial using gemogenovatucel-T (Vigil), a novel immunotherapy vaccine. We will measure DNA damage within the clinical trial patients and in matched archived ovarian tumor samples. We will then validate the predictive value of DNA damage for therapeutic response by examining how low or high DNA damage correlates with overall survival and progression-free survival for immunotherapy vs. standard of care. DNA damage will also be associated with immune responses to develop a specific biomarker predictive for immunotherapy use. To improve outcomes from ovarian cancer patients, we must tailor treatment to their tumors. The proposed work will test a novel clinical assay that can be employed rapidly in a clinical setting to measure DNA damage within a tumor. These measurements will assess DNA repair function within a tumor and offer a new biomarker for stratifying patients. Stratifying patients with clinically meaningful biomarkers is vital to improving therapeutic responses and increasing progression-free and overall survival in ovarian cancer. Current molecular testing has failed to generate useful biomarkers for ovarian cancer patients. Our novel assay provides a more functional assessment of active repair mechanisms to identify those tumors with more immunogenic landscapes that would benefit from immunotherapies. The proposed work will improve patient stratification for primary and secondary therapies by offering new and patient-specific biomarkers for DNA repair. Our long-term goal is to reduce recurrence in ovarian cancer and extend survival, and this work is an essential step in personalizing ovarian cancer treatment to achieve this goal.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110596
Entities
People
- Natalie Gassman
Organizations
- United States Army
- University of South Alabama