Massachusetts General Hospital
Molecular Biologist, Center for Cancer Research
Co-Director, Circulating Tumor Cell Laboratory
Professor of Surgery, Harvard Medical School
Identifying treatment strategies that will improve response to androgen receptor-targeting drugs in patients with triple-negative breast cancer.
There is growing interest in using prostate cancer drugs for triple-negative breast cancer (TNBC). While TNBCs do not possess common breast cancer hormone receptors (such as estrogen and progesterone) some TNBCs generate the androgen receptor (AR) and respond to the androgen hormone—not unlike prostate cancer cells—which can drive their progression. While this makes for a promising therapeutic target, one of the challenges in treating TNBC with any targeted therapy (a drug designed to act upon a single receptor or other protein in the body) is the inherent diversity in the molecular makeup of cells within a single TNBC tumor. This “intra-tumor 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 research is to understand how AR heterogeneity affects tumor progression and response to AR therapy, and to leverage that information to generate new therapeutic strategies that will eradicate all cells within a heterogeneous tumor.
Dr. Maheswaran and her team captured circulating tumor cells—cells that escaped the original tumor and entered the bloodstream—from a patient with TNBC. They divided the cells into two different types: those with several copies of the AR gene (AR-amplified) and those with the normal number of AR gene copies, grew them in the laboratory and performed molecular analysis to decipher how these different cells may function within a single tumor. Their findings show that AR-amplified TNBC cells may alter the infiltration of immune cells into the tumor and thus influence breast cancer growth. They also found that AR-amplified cells respond to androgen in an unexpected way, which could have implications for the response of these cells to AR-blocking therapies.
The team will continue to study these two cell populations, exploring their sensitivity to AR therapy and identifying potential molecular vulnerabilities that can be targeted with combination therapy strategies.
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).
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