Moving PARP Inhibitors Beyond BRCAness as Immune Modulating Agents for TNBC Prevention
Abstract
Despite the advances in the treatment of breast cancer, too many women with breast cancer must undergo chemotherapy, and still some women still die of this disease. To eliminate this disease, we seek to develop effective, but minimally toxic, ways to prevent this disease and eliminate the need for toxic chemotherapy. Basic science research has uncovered new information about breast cancer biology and the immune system that now supports the development of targeted therapies for breast cancer treatment and prevention. Clinical trials have shown that estrogen receptor (ER)-positive breast cancer prevention is possible, although this preventive therapy is still too toxic for most women. However, there are no preventive therapies for triple-negative breast cancer (TNBC), the most aggressive form of breast cancer that occurs often in young women, African American women, and women who carry BRCA1 mutations. In this study, we will test novel targeted therapies for the ability to alter immune pathways and to prevent TNBC development in mice. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) are approved for the treatment of advanced breast tumors with BRCA1 or BRCA2 (BRCA1/2) mutations. In March 2022, the U.S. Food and Drug Association (FDA) approved PARPi (Olaparib) for the adjuvant treatment of high-risk early breast cancer in women with BRCA mutations. Consistent with this notion, recent studies have shown that PARPis can prevent the development of BRCA1-deficient TNBC tumors in mice. However, women with germline BRCA1/2 mutations are a very small subset of women that develop TNBC. Laboratory studies from our group uncovered a previously unknown activity of PARPis. We have shown that PARPis activate the immune system through an important pathway called the c-GAS-STING- type I IFN innate immune response pathway. Our preliminary data suggest that the efficacy of PARPis is through regulating the expression of a key immune gene, STING, which suggests that PARPis will prevent many TNBCs, and not just those arising in women carrying BRCA1/2 mutations. Based on results from our clinical and laboratory studies, we wish to now study the following: (1) Determine how PARPis induce the expression of the key immune gene STING and how they affect the innate immune response, (2) Determine whether PARPis induce changes in the c-GAS-STING-type I IFN innate immune response pathway, which can serve as biomarkers for PARPis’ ability to induce anti-tumor immunity, (3) Evaluate whether PARPis prevent the development of TNBC in two mouse models (one that develops BRCA1-deficient tumors and one that develops BRCA1 wild-type tumors). Upon completion of this project, we will obtain essential preclinical data to support the development of clinical trials to test the ability of PARPis to prevent the development of all TNBCs, not just those that arise due to BRCA1/2 mutations. In this application, we study PARPis in TNBC models as proof-of-principle experiments. Innate immune response is a fundamental biological pathway in cancer immunology of all breast cancer subtypes and in breast cancers at all development and progression stages. By identifying the new mechanisms underlying PARPis’ ability to activate the innate immune system, our study will benefit breast cancer patients, women at risk of TNBC, as well as women who develop this devastating disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310055
Entities
People
- Powel Brown
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army