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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 who relapse with estrogen receptor (ER)-positive endocrine treatment-resistant 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 SLC7A5, a protein involved in transporting the amino acid leucine inside the cell, plays a role in the development of drug-resistance in ER-positive breast cancer. Understanding how SLC7A5 renders endocrine resistance could identify a new strategy for overcoming resistance in patients with therapy resistant ER+ cancers.
What’s next: Dr. Muthuswamy will investigate how SLC7A5 reprograms cellular metabolism in ER+ breast cancer cells and investigate if inhibiting SLC7A5 or any downstream metabolic enzymes can overcome therapy resistance.
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 ends. 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 SLC7A5 mediated leucine amino acid transport 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: Of the women who die from breast cancer every year, most succumb to metastatic ER-positive disease, and resistance to endocrine treatments is the primary driver of cancer progression and mortality in these patients. Dr. Muthuswamy’s investigations into metabolic vulnerabilities to combat endocrine resistance may provide new treatment options that would reduce mortality.
Current investigation: He and his team are following up on their observation that leucine is a driver of endocrine resistance. In the first phase of this work, they will develop patient derived organoid cultures from patients with endocrine-resistant breast cancer.
What he’s learned so far: He and his team have discovered an unexpected correlation between levels of the amino acid leucine and the increase of tamoxifen resistance in ER-positive tumors. Their study showed that lowering leucine levels decreased the growth of new cancer cells, while increasing leucine raised it—suggesting that a diet low in this amino acid could be beneficial for patients with ER-positive breast cancer.
What’s next: Dr. Muthuswamy will continue his work on creating endocrine-resistant models of breast cancer. He’ll also investigate how leucine metabolism promotes endocrine resistance and identify new vulnerabilities for combating it.
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.