Gaorav Gupta, MD, PhD
Chapel Hill, North Carolina
University of North Carolina
Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina
American Society for Radiation Oncology
Revealing the molecular drivers of triple-negative breast cancer in order to select the right treatment for each patient.
Estrogen receptor-positive and HER2-positive breast cancers are treated with targeted therapies, which are drugs designed for their unique molecular makeup, e.g., therapies that affect hormone signaling in ER-positive tumors, and HER2-targeted drugs for HER2-positive tumors. Until recently, triple-negative breast cancer (TNBC) did not have any targeted therapies, but further molecular characterization of TNBC identified vulnerabilities that could serve as drug targets. Subsequently, new treatments emerged, including PARP inhibitors for TNBC caused by mutations in BRCA genes, immunotherapy drugs, and hormone therapies that target the androgen receptor. In spite of these successes, not all patients derive the same benefit from these treatments. For his American Society for Radiation Oncology award, sponsored by BCRF, Dr. Gupta and his team are pursuing new molecular markers that may be used to predict a tumor’s response, so that patients receive the right treatment for their breast cancer.
The main focus of their research is the process of DNA repair that often malfunctions during the development of TNBC. Dr. Gupta’s team developed a series of laboratory models to study how these malfunctions affect response to treatment, using a new gene-editing technology called CRISPR. CRISPR allowed the team to manipulate several DNA repair genes at once; and it will make it easier to track which tumor cells survive therapy, and which respond to therapy.
In preliminary research, the team identified a potential driver in the resistance to DNA damaging drugs as well as immunotherapy. The team will use their 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.
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