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Gaorav Gupta, MD, PhD
University of North Carolina
Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina
American Society for Radiation Oncology
Goal: The goal of this project is to better understand the molecular drivers of triple negative breast cancer (TNBC) in order to select the right treatment for the right patient.
Impact: Dr. Gupta’s research focuses on a molecular pathway that normally protects the DNA in our cells but malfunctions during the development of TNBC. His team has developed a series of laboratory models to study how these malfunctions affect response to treatment with the hope of learning how to predict response and block development of resistance.
What’s Next: Dr. Gupta will use a CRISPR-enhanced triple negative breast cancer model to characterize the therapeutic sensitivity profile of breast cancers with different mutations in the DNA damage response pathway.
The past few years have witnessed the emergence of new treatment options for patients with triple negative breast cancer (TNBC). PARP inhibitors and immunotherapy have been FDA-approved for selected subsets of TNBC patients. More exciting treatments are currently under clinical investigation. This progress is truly incredible and indicates that we are on the right path. Ultimately, the insights gained from this project will provide a means for personalizing therapy for patients with TNBC, and for identifying new therapies in situations where are current treatments are unsuccessful.
Full Research Summary
Research Area: Dr. Gutpa’s work is focused on understanding the mechanisms underlying drug resistance in breast cancer, particularly triple negative breast cancer (TNBC). He uses genetically engineered model systems to study the effect of gene mutations in DNA repair pathways and how these affect tumor response to treatment.
Impact: The recent molecular characterization of triple negative breast cancer revealed distinct molecular classifications of this subgroup of breast cancer and identified vulnerabilities that could be potential new drug targets. Subsequently new treatments approaches have emerged to leverage these vulnerabilities. Examples include PARP inhibitors for treatment of TNBC caused by mutations in the BRCA genes, immunotherapy drugs called checkpoint inhibitors, and hormone therapies that target the androgen receptor. In spite of these successes, not all patients derive the same benefit from these treatments and others will become resistant after initial response. Dr. Gupta is conducting studies aimed at identifying molecular markers that may be used to predict response to a drug, so that patients receive the right treatment for their breast cancer.
Current Investigation: Dr. Gupta has created a CRISPR model of TNBC allowing him to test the effect of specific mutations in DNA repair pathway genes on response to treatment. In preliminary research, he identified a potential driver in the resistance to DNA damaging drugs as well as immunotherapy. In his American Society for Radiation Oncology award, sponsored by BCRF, he will utilize his CRISPR model system to further elucidate the role of this protein and determine whether it could serve as a biomarker to predict which patients are likely to benefit from a specific therapy.
Gaorav Gupta, MD, PhD is currently Assistant Professor in the Department of Radiation Oncology at the University of North Carolina at Chapel Hill. His research lab, based in the Lineberger Comprehensive Cancer Center, studies mechanisms and vulnerabilities of genome instability in breast cancer. His lab discovered an “addiction” to DNA polymerase theta in breast cancers that harbor mutations in over 100 different DNA repair genes, including BRCA1 and BRCA2. More recently, his lab developed a CRISPR-enhanced model for triple negative breast cancer that they used to identify molecular vulnerabilities of Mre11-deficient breast cancers that may be therapeutically exploited. Dr. Gupta will use this CRISPR-enhanced triple negative breast cancer model to more broadly characterize the therapeutic sensitivity profile of breast cancers with different mutations in the DNA damage response pathway. Concurrently, his lab is working to develop and validate blood- and tissue-based biomarkers in breast cancer to facilitate precision oncology. Dr. Gupta is also co-Principal Investigator of a multi-institutional clinical trial of pre-operative radiotherapy and immunotherapy in lymph node-positive breast cancer. His long-term vision is to improve the safety and efficacy of DNA-directed therapy for breast cancer through basic science, translational research, and biomarker-guided clinical trials.
Dr Gupta received his MD, PhD from the Weill Cornell/Memorial Sloan Kettering/Rockefeller University Tri-Institutional Program. He completed his graduate work with Dr. Joan Massagué, where he elucidated mechanisms for tissue-specific metastasis in breast cancer. He subsequently completed residency training in Radiation Oncology at Memorial Sloan Kettering Cancer Center and served as chief resident during his final year. He completed postdoctoral research in the lab of John Petrini, where he demonstrated a critical role for the DNA damage sensor protein Mre11 in breast cancer prevention.