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Senthil Muthuswamy, PhD
Director, Program in Cell Biology,
Beth Israel Deaconess Medical Centre,
Associate Professor, Department of Medicine,
Harvard Medical School
Goal: To identify new treatment options for patients with estrogen receptor (ER)-positive breast cancer.
Impact: Many ER-positive tumors become resistant to existing anti-estrogen (endocrine) treatments, allowing cancer to return or spread. Dr. Muthuswamy has discovered that the amino acid leucine may play a role in the development of treatment resistance in ER-positive breast cancer. This finding could lead to a new strategy for overcoming resistance in patients.
What’s next: Dr. Muthuswamy will investigate how leucine promotes endocrine resistance and what strategies may prevent this from occurring.
While ER-positive breast cancers have the best prognosis at five years, women diagnosed with ER-positive breast cancer have a sustained risk of recurrence many years after treatment. The primary cause of cancer progression and death in these patients is the development of resistance to endocrine therapy, highlighting the urgency for new treatments. Dr. Muthuswamy’s study of leucine has opened a new avenue of investigation to combat endocrine resistance.
Full Research Summary
Research area: Pursuing ways to combat the development of resistance to endocrine treatments in patients with estrogen receptor (ER)-positive breast cancer.
Impact: Among the greater than 42,000 women that die from breast cancer every year, 70-80 percent of them die from ER-positive disease that has spread to other organs. The development of resistance to treatments, including recently employed treatment strategies such as CDK4/6 inhibitors, is the primary driver of cancer progression and mortality in these patients. Dr. Muthuswamy has found that the amino acid leucine is a potential driver of endocrine resistance. He and his colleagues are conducting investigations into the role of leucine in this process. To conduct these studies, Dr. Muthuswamy and fellow BCRF-researcher Dr. Myles Brown 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 metabolic vulnerabilities in ER-positive breast cancer that may combat endocrine resistance and provide new treatment options to reduce mortality for these patients.
Current investigation: Dr. Muthuswamy and his team are continuing their investigations into leucine as a mediator of endocrine resistance and are utilizing their models to further characterize factors that may reduce endocrine resistance.
What he’s learned so far: He and his team have discovered an unexpected correlation between the levels of the amino acid leucine and tamoxifen resistance 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 has been shown to be a factor in the development of resistance to both anti-estrogen treatment with tamoxifen, as wells as CDK4/6 inhibitor treatment.
What’s next: In the next year, Dr. Muthuswamy and his colleagues will build on their discoveries by investigating the mechanisms by which SLC7A5 overexpression confers resistance to endocrine agents and CDK4/6 inhibitors and to identify new vulnerabilities for combating this drug resistance. His team will utilize their expertise in developing patient-derived model systems to develop endocrine- and Palbociclib-resistant models of breast cancer for these studies. In addition, Dr. Muthuswamy will develop a new immune-oncology strategy for targeting breast cancer to personalize treatment for ER-positive breast cancer patients.
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.