Identification of Tumor Chemoresistance Signatures in BRCA-Deficient Models and Patients
Abstract
The poor prognosis of ovarian cancer patients is primarily due to their diagnosis at advanced stages and the development of resistance to therapy. Patients with mutations in the BRCA1 and BRCA2 genes are more sensitive to platinum and PARP inhibitor therapy due to defects in homologous recombination-based DNA repair pathways. PARP inhibitors have shown great promise in BRCA patients when tested in ongoing Phase I and Phase II clinical trials. However, a substantial percentage of these patients are non-responsive and exhibit tumor progression despite therapy. The mechanisms underlying intrinsic and acquired resistance to PARP inhibitors are not well elucidated. The results of our studies can have significant implications for the Phase III clinical trials currently underway and the clinical management of patients using PARP inhibitors as a monotherapy or in combination with platinum and anti-angiogenic compounds. Resistance to chemotherapy is thought to be mediated in part by cancer stem cells, which are enriched in recurrent tumors. The effect of PARP inhibition on these cells has not been studied in ovarian cancer although a few reports exist in other cancers. A recent study carried out in triple-negative breast cancer showed that cancer stem cells are only marginally depleted upon treatment with PARP inhibitors, suggesting that cancer stem cells may be resistant to PARP inhibition. Consequently, determining if cancer stem cells play a key role in mediating PARP resistance can offer new avenues to design better strategies for therapy in newly diagnosed and recurrent patients. Our proposal aims to identify the molecular signatures of therapeutic resistance in recurrent tumors and cancer stem cells using unique murine models of high-grade serous cancers that harbor mutations in BRCA genes. A detailed characterization of ovarian tumors as they transition from sensitive to recurrent, resistant disease will help in designing better strategies for targeted therapeutic intervention. We will address our hypothesis by carrying out whole genome analysis to study the genetic, epigenetic (miRNA), and transcriptomic alterations in whole tumors and cancer stem cells isolated before and after treatment with carboplatin, PARP inhibitors, and anti-angiogenic inhibitors, such as Cediranib. The results obtained from the murine models will be validated in BRCA patient samples for clinical translation. In the short term, we will develop a non-invasive serum-based assay to evaluate prognostic and predictive biomarkers for response to PARP inhibitors and identify genetic signatures associated with intrinsic or acquired resistance to PARP therapy. In the long term, this study will set the stage to test different inhibitors to resistance pathways identified in the proposed study. The newly identified inhibitors can be used to treat women carrying BRCA mutations who have failed chemotherapy and/or treatment with PARP inhibitors. The proposed work is both innovative and high impact due to the substantial clinical significance of finding more efficient and less toxic personalized treatments to eradicate tumors. Our studies will test new paradigms for tumor treatment using PARP inhibitors and could greatly improve the high rate of therapeutic failure and tumor relapse currently seen in ovarian cancer. The proposed studies are within the stated mission and goals of the Department of Defense Ovarian Cancer Research Program to reduce cancer mortality rates through better, less toxic therapies. Data collected from these key studies could be instrumental in the design of new human clinical trials for ovarian cancer specifically targeting patients with BRCA mutations or defects in DNA repair pathways. As the daughter of a Gynecological Oncologist, I have a heightened awareness and understanding of how many women and their families struggle with this devastating disease. I feel compelled to carry on their fight with compassion and deter
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510089
Entities
People
- Daniela Dinulescu
Organizations
- United States Army