Identifying Therapeutic Vulnerabilities of Bone Marrow-Driven Recurrence of ER+ Breast Cancer
Abstract
Patients with estrogen receptor-positive (ER+) breast cancer face an ongoing, long-term risk of recurrent, metastatic disease. Current endocrine therapies may suppress, but not eliminate, ER+ breast cancer cells from sites such as bone marrow, the most common location for metastases. The bone marrow environment itself is a major contributor to the ability of ER+ breast cancer cells to resist endocrine therapies. One type of bone marrow stromal cell type, known as mesenchymal stromal cells (MSCs), appears to be particularly important in determining the effects of therapy on ER+ breast cancer cells. Most studies suggest that interactions with MSCs allow ER+ breast cancer cells to survive therapy, but how MSCs increase drug resistance of breast cancer cells in bone marrow remains unclear. Discovering how interactions with MSCs allow breast cancer cells to survive in bone marrow will open new approaches to prevent recurrent, metastatic disease and improve outcomes for patients. Our research will address this important problem in ER+ breast cancer with the goal of identifying approaches to treatment that will successfully eliminate these cancer cells from bone marrow. We will focus on testing approved drugs or compounds currently in clinical trials for cancer to shorten the time frame to clinical translation to three years or less. Our initial research in cell-based studies shows that MSCs cause major shifts in ER+ breast cancer cells. When grown with MSCs, ER+ breast cancer cells decrease expression of the estrogen receptor, making the cancer cells resistant to clinically used endocrine therapies. MSCs cause ER+ breast cancer cells to increase activities of pathways promoting proliferation and survival, and breast cancer cells change the pathways they use to produce cellular energy. We also found that MSCs shift ER+ breast cancer cells to less-differentiated, stem-like cells commonly known as cancer stem-like cells (CSCs). All of these changes to ER+ breast cancer cells account for their resistance to standard therapies and may appear to make it impossible to eliminate cancer cells from bone marrow. However, we believe changes that MSCs cause in ER+ breast cancer cells expose new vulnerabilities of these cells that we can exploit for therapy. The challenge is to identify these vulnerabilities and approaches to successfully target them with minimal toxicity to other cells. Our experimental approach is designed to accomplish these goals. By analyzing changes in gene expression and metabolism in ER+ breast cancer cells grown with MSCs, we have identified promising new vulnerabilities of cancer cells. We have selected inhibitors that target specific changes in ER+ breast cancer cells. To test our new treatment approaches, we need a model system that allows us to test multiple treatment options in a format that closely models bone marrow in patients. Our research group has pioneered a technology for establishing 3D models of tumor environments, such as bone marrow, that enable us to co-culture ER+ breast cancer cells with MSCs. These 3D models reproduce normal mechanical properties and extracellular proteins present in bone marrow in a microscale format. As compared with standard cell-based assays, 3D models better predict treatments that will succeed in patients. We can test hundreds of different treatment combinations using a robotic system, using both advanced imaging and biochemical readouts to measure effects of therapy on cancer cells and MSCs. With this drug testing technology, we also will measure how cancer cells respond over several weeks of treatment. The ability to extend treatment for weeks, rather than only a few days as done in most drug testing studies, is a unique capability that better simulates treatment in patients. We will test treatments targeting promising new therapeutic vulnerabilities in cell signaling, CSCs, and pathways cancer cells adopt to produce energy. Our objective is
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210120
Entities
People
- Gary Luker
Organizations
- United States Army
- University of Michigan