Identifying the Determinants of Clinical Responses to PARP Inhibitors in Ovarian Cancer Immunotherapy
Abstract
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are approved for the treatment of ovarian cancer in the maintenance setting, as well as for advanced ovarian tumors harboring BRCA1 or BRCA2 (BRCA1/2) mutations. Interestingly, studies from our group and others have shown that PARPis promote the accumulation of cytosolic DNA fragments due to unresolved replication-associated DNA lesion and activate the DNA sensing cyclic GMP-AMPSynthase (cGAS)-stimulator of interferon genes (STING) pathway-mediated type 1 interferon (IFN) response. Our clinical trial data have demonstrated promising patient benefit with durable radiological responses with this combinatorial regimen of PARPi+PD-1/L1i, but not all patients benefited from this combination. Our proposed research in this application is to identify molecular determinants of the immune-modulatory functions of PARPis and to develop clinically applicable biomarkers to predict PARPi therapeutic efficacy in potentiating immune checkpoint blockade (ICB). This goal will be achieved by addressing the specific aims: (1) Determine if the alteration of the immune checkpoint regulatory molecule B7-H3 in ovarian tumor cells is associated with PARPi-induced immune responsiveness and can be developed as a biomarker for determining the therapeutic efficacy of PARPis as immunomodulatory agents. (2) Determine if alterations of cGAS-STING-type I IFN-dependent innate immune response pathway in ovarian tumor cells are associated with PARPi-induced immune responsiveness and can be developed as biomarkers for determining the therapeutic efficacy of PARPis as immunomodulating agents. (3) Characterize the transcriptional landscape in tumor immune microenvironment induced by PARPis by using single cell genomics in ovarian cancer patient specimens.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2023
- Accession Number
- AD1213444
Entities
People
- Guang Peng
- Timothy A Yap
Organizations
- The University of Texas MD Anderson Cancer Center