Identifying the Determinants of Clinical Responses to PARP Inhibitors in Ovarian Cancer Immunotherapy
Abstract
Although immunotherapy drugs called PD-1 or PD-L1 inhibitors (PD-1/L1i), which prime the body’s immune system to attack cancer, are effective in different cancers, only around 8% of ovarian cancer patients benefit from immunotherapy. Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are approved for the treatment of ovarian cancer in patients responding to platinum-based chemotherapy in the maintenance setting, as well as for advanced ovarian tumors with BRCA1 or BRCA2 (BRCA1/2) mutations. Recently, a range of clinical trials have been started to test the combination of PARPis and PD-1/L1is (PARPi+PD-1/L1i ) in ovarian cancer patients. Patient benefit with long-term clinical responses with this combination treatment of PARPi+PD-1/L1i has been demonstrated in selected patients. However, only a subset of patients responded to this combination regimen, and there were no clear indicators as to how one could predict for patients who could respond, including the use of BRCA1/2 and other related mutations. Therefore, the main goal of our application is to identify, using laboratory tests, which ovarian cancer patients may benefit from the combined treatment of PARPi+PD-1/L1i, so as to prolong the lives of ovarian cancer patients. To achieve this goal, we have already used cutting edge technologies (called single cell RNA-sequencing technology, which has enabled us to understand more about ovarian cancer genes at the single-cell level and how they differ across thousands of cells within a cancer sample) and computational approaches to identify individual tumor characteristics that can be used to predict which patients will benefit from the combination of PARPi+PD-1/L1i through PARPi-induced immune responses (i.e., using PARP inhibitors to boost the effects of PD-1/L1is). Based on results from our clinical and laboratory studies, we now wish to: 1. Determine whether an abnormality in the protein B7-H3 in ovarian tumor cells is associated with PARPi-induced immune responsiveness and can be developed as a biomarker to identify patients who will benefit from the combination of PARPi+PD-1/L1i. 2. Determine whether abnormal signaling along an important pathway in our immune system (called the c-GASSTING-type I IFN innate immune response pathway) in ovarian tumor cells are linked with PARPi-induced immune responsiveness and can be developed as a biomarker to identify patients who will benefit from the combination of PARPi+PD-1/L1i. 3. Determine whether abnormalities in the protein biomarker B7-H3 and the c-GAS-STING-type I IFN pathway detected and monitored in blood and cancer samples obtained from ovarian cancer patients treated in ongoing clinical trials of the combination of PARPi+PD-1/L1i are predictive of better clinical outcomes. The B7-H3 biomarker and the c-GAS-STING-type I IFN pathway we propose to study are important cellular processes that are found in all ovarian cancer subtypes and stages. We thus expect that the new biomarker detection test we develop for patients will be able to individualize the selection of patients who have an increased chance of benefiting from the combination of PARPi+PD-1/L1i and benefit ovarian cancer patients across different subtypes and stages. These predictive biomarkers are completely novel and are not dependent on the traditional abnormalities, such as BRCA1/2 mutations. Importantly, these new biomarkers will broaden the use of PARPis to ovarian cancer patients who do not have BRCA1/2 mutations.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110282
Entities
People
- Timothy A Yap
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army