Sheheryar K. Kabraji, BM BCh
Dana-Farber Cancer Institute – Harvard Medical School
While effective HER2-targeting drugs have greatly improved outcomes for patients with HER2-positive (HER2+) breast cancer, relapse and recurrence still occur. When HER2+ breast cancer returns after treatment, it is because some cancer cells survive killing, and are known as minimal residual disease (MRD). To study the biology of MRD we have developed a mouse model of HER2+ breast cancer (t-HER2) where we can turn on and turn off tumor formation at will. This model also has an intact immune system, making it ideal to study tumor-immune interactions. When we turn off tumors, we model the scenario in patients where tumors shrink with effective therapy. However, like in some patients, tumors recur spontaneously in our model. Using the t-HER2 model we found that MRD is comprised of rare ‘sleeping’, or quiescent, cancer cells surrounded by signs of a suppressed anti-tumor immune response. We hypothesize that MRD after anti-HER2 treatment occurs because drug-resistant quiescent cancer cells dampen the anti-tumor response. Our objective is to eliminate MRD after HER2 therapy by stimulating an anti-tumor immune response. To achieve this goal, we will first investigate the immune changes seen when tumors shrink to MRD in the t-HER2 model. Next, we will study how the AKTlow quiescent cancer cell (QCC) suppresses the anti-tumor immune response in the setting of MRD. Finally, we will test whether using immunotherapy can prevent tumors from recurring after they shrink with HER2 inhibition. This study will suggest new ways to identify patients at risk for MRD and help understand how rare, quiescent cancer cells contribute to tumor drug-resistance. Our results could be readily translated into a novel clinical trial using a QCC-targeting drug + immunotherapy to prevent relapse and recurrence in patients with HER2+ breast cancer.
Dr Sheheryar Kabraji received his medical degree from Oxford University Medical School and completed internal medicine residency at Massachusetts General Hospital. As a medical oncology fellow in the Dana Farber/Partners Hematology/Oncology Fellowship Program, he undertook post-doctoral research in the laboratory of Sridhar Ramaswamy at the Mass General Cancer Center where he demonstrated that AKTlow quiescent cancer cells can be found in residual breast tumors after neoadjuvant chemotherapy.
Dr Kabraji is a breast medical oncologist at the Susan F. Smith Center for Women’s Cancers, Dana Farber Cancer Institute, and Instructor in Medicine at Harvard Medical School. Dr Kabraji’s research in the Zhao Laboratory at Dana Farber Cancer Institute focuses on cancer cell quiescence as a mechanism of tumor drug resistance in localized and metastatic breast cancer.