Senthil Muthuswamy, PhD
Associate Professor, Medicine, Harvard Medical School
Director of Cell Biology at Cancer Center, Medicine, Beth Israel Deaconess Medical Center
Harvard Medical School
Combating the development of resistance to endocrine treatments in patients with estrogen receptor-positive breast cancer.
Among the greater than 42,000 women that die from breast cancer every year, 70-80 percent of them die from estrogen receptor (ER)-positive disease that spread to other organs. The development of resistance to treatments, including recently employed strategies such as CDK4/6 inhibitors, is the primary driver of cancer progression and mortality in these patients. Dr. Muthuswamy, fellow BCRF-researcher Dr. Myles Brown, and their teams developed laboratory models that more accurately reflect the inter-patient variation commonly seen in ER-positive breast cancer in the clinic. These models will be utilized to discover vulnerabilities in ER-positive breast cancer that may combat endocrine resistance and provide new treatment options to reduce mortality for these patients.
Dr. Muthuswamy and his team discovered an unexpected correlation between the levels of the amino acid leucine and resistance to tamoxifen in ER-positive tumors. They showed that the amount of leucine was associated with the growth of cancer cells, an effect that may be driven by the leucine transporter SLC7A5 which is a factor in the development of resistance to both anti-estrogen treatment as well as CDK4/6 inhibitor treatment. During the last year, the team pursued the mechanisms by which SLC7A5 promotes resistance to CDK4/6i and found a relationship between glucose metabolism and CDK4/6i resistance.
Capitalizing on their discovery of the relationship between glucose metabolism and CDK4/6i resistance, the team will next pursue metabolic vulnerabilities to combat drug resistance in ER-positive breast cancer. In addition, they will use patient derived laboratory models that incorporate immune cells to develop immune-oncology strategies for the treatment of ER-positive breast cancer, with a focus on an immune cell subtype known as gamma/delta T cells.
“Our exploratory and bold initiative to develop an immunotherapy strategy against breast cancer is off to a great start due to the support from BCRF.” – Dr. Muthuswamy
Senthil K. Muthuswamy, Ph.D., is the Director of the Cell Biology Program at the Cancer Centre at Beth Israel Deaconess Medical Centre, Harvard Medical School. Dr. Muthuswamy received his Ph.D. from McMaster University, Canada and did his postdoctoral fellowship with Joan Brugge at Harvard Medical School. He began his independent faculty position at Cold Spring Harbor Laboratory, New York and subsequently moved to Princess Margaret Cancer Centre as the Margaret Lau Chair in Breast Cancer Research. In 2015, he moved to BIDMC to direct the Cell Biology program at the Cancer Center at BIDMC. Dr. Muthuswamy is a recipient of Rita Allen Scholar award, V Foundation scholar award, US Army Era of Hope Scholar Award, and the Canadian Society of Biochemistry and Molecular & Cellular Biology young scientist award for outstanding research achievements.
His laboratory pioneered both the development and use of three-dimensional culture methods for modeling carcinoma of breast and pancreas and understanding the unexplored role played by cell polarity proteins in regulating the biology of cancer. He was the first to identify cell polarity proteins, such as PARD6, PARD3 and SCRIB, as critical regulators of cell death, cell proliferation and metastasis either by themselves or in cooperation with oncogenes, such as ERBB2 and MYC, in breast cancer. His group continues to investigate and discover how cell polarity proteins regulate cell biology of cancer and normal cells and its impact on stress adaptation and therapy resistance.
He recently launched a new initiative in his lab to bridge cancer biology and clinical cancer care, called “Microscope to Stethoscope”. His team is developing and implementing personalized tumor organoid culture platforms to assist patients and oncologists by performing a lab-based screen of available treatment options to identify the best possible cancer treatment for each patient. This effort is married to his long-standing interest in using patient-derived tumor models for translational and discovery research to find better cancer treatments.
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