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Shyamala Maheswaran, PhD
Associate Professor of Surgery
Co-Director, Circulating Tumor Cell Laboratory
Massachusetts General Hospital
Goal: To identify treatment strategies that will improve response to androgen receptor (AR) targeting drugs in patients with triple negative breast cancer (TNBC).
Impact: TNBC is an aggressive breast cancer with few treatment options. While it is not driven by estrogen, some TNBC depend on androgens—male hormones—to grow. This has garnered considerable interest in treating TNBC with anti-androgen drugs. Dr. Maheswaran is conducting studies aimed at improving response to this new targeted therapy for women with TNBC.
What’s next: Dr. Maheswaran and her team will apply molecular tools to decipher how different cell types within a tumor respond differently to androgen receptor-targeting drugs.
Hormone receptor (HR)-positive breast cancers respond well to drugs that target the hormone receptor. Examples are tamoxifen and aromatase inhibitors to block the activity of the estrogen receptor. Conversely, TNBC lack the common hormone receptor targets in breast cancer, leaving these patients with fewer therapeutic options. Some TNBC, however, rely on a different hormonal receptor, the androgen receptor (AR), and agents that target AR are now being tested for the treatment of TNBC. Dr. Maheswaran and her team are conducting laboratory studies to develop strategies to make these treatments an effective option for patients with TNBC.
Full Research Summary
Research area: Improve options for TNBC patients and discover new treatment strategies for improved efficacy of androgen receptor (AR)-targeting drugs.
Impact: There is growing interest in using prostate cancer drugs for triple negative breast cancer (TNBC). Like prostate cancer cells, some TNBC have been shown to respond to androgens through androgen receptors. One of the challenges in treating TNBC with any targeted therapy is the inherent diversity in the molecular makeup of cells within a single TNBC tumor. This “intra-tumoral heterogeneity” causes variability in response to treatment, in which some cells are killed by the drug but other cells survive. The goal of Dr. Maheswaran’s BCRF research is to improve response to AR-targeting drugs with novel drug combinations.
Current investigation: Dr. Maheswaran and her team will capture circulating tumor cells (CTCs)—cells that have escaped the original tumor and entered the circulation—from patients with TNBC. They will then isolate the cells with AR from those without AR and study their response to an anti-AR drug called enzalutamide. From these findings they hope to understand how these cell types interact to affect response to the AR therapy and what combination approaches could improve response in order for anti-AR therapy to be an effective treatment option for patients with TNBC.
Dr. Shyamala Maheswaran’s research is focused on defining the molecular mechanisms that drive breast cancer progression and metastasis.
Breast cancer, initially confined to the primary site, eventually spreads to distal sites, including lung, liver, bone and brain, by invading into the bloodstream. Upon reaching these distal sites, the tumor cells continue to grow and evolve well after removal of the primary tumor resulting in overt metastasis and disease recurrence, the leading causes of cancer-related deaths.
Using cell culture, laboratory models and patient-derived tissues and circulating tumor cells (CTCs) enriched from breast cancer patients’ blood, Dr. Maheswaran's laboratory characterizes the contribution of oncogenic cues, tumor microenvironment-derived signals, epithelial to mesenchymal transition and tumor heterogeneity to breast cancer progression and therapeutic responses. She collaborates closely across several disciplines, including Clinicians and Engineers at MGH and is currently the Co-Director of the Circulating Tumor Cell Laboratory at the Massachusetts General Hospital (MGH).