Targeting Cancer Stem Cells in Triple-Negative Breast Cancer
Abstract
Overarching Challenges: 1) Identify determinants of breast cancer initiation, risk or susceptibility. 2) Revolutionize treatment regiments by replacing them with ones that are more effective, less toxic and impact survival. Conventional anticancer therapies target cancer cells that have sufficient access to oxygen and are rapidly growing. However, there are at present no approved therapies that target cells that lack oxygen (hypoxic cells). Yet there is growing evidence that a rare population of hypoxic cancer stem cells are the cells that give rise to tumors and drive tumor cells to invade surrounding tissue and move to metastatic sites in other tissues. Cancer stem cells have the ability to renew themselves and give rise to highly proliferating tumor cells, but they also have multiple ways to avoid being killed by drugs, radiation, some targeted therapy, and even immune-based therapy. Cancer stem cells are largely the cells that cause resistance to therapy and tumor recurrence. Thus, we need novel therapies designed to kill these hypoxic cancer stem cells. We also need ways of determining which patients will respond to conventional therapy and which patients will require these novel therapeutic treatments targeting cancer stem cells. Our proposal, if successful, will accomplish both of these goals. We have identified a novel drug target, BACH1, that controls the survival of these cancer stem cells. We have also shown that we can repurpose a drug already on the market to deplete BACH1 from tumors, decrease the population of cancer stem cells in breast tumors, and increase tumor killing by therapies such as radiation. Furthermore, the tissue microarray assay we are developing should identify which patients will benefit from conventional therapy and those more likely to respond to novel therapy that targets BACH1. Thus, we have a means of identifying and matching patients with therapies appropriate for their tumors. Our approach is a particularly important for sensitizing normally resistant tumors to both radiation treatment and chemotherapy. The therapeutic combinations we are testing (radiation or chemotherapy and the BACH1 targeting drug) are already on the market and therefore previously tested for patient tolerance. However, the drugs are toxic by nature and therefore would likely be used in more acute treatment regimens rather than chronic treatments. The timeline for using this treatment is limited only by the need for preclinical studies to show proof of principle and clinical trials to demonstrate efficacy. Once this has been accomplished (a few years), this treatment could be immediately used for patients. In this proposal, we have focused on triple-negative breast cancer (TNBC), the most aggressive, metastatic, and treatment-resistant subtype of breast cancer. However, BACH1 is also expressed in other subtypes of breast cancer such as hormone-positive tumors. Although this treatment will not eliminate all breast cancer, the approach we are developing should help at least 2/3 breast cancer patients benefit from more appropriate treatment.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110120
Entities
People
- Marsha Rosner
Organizations
- United States Army
- University of Chicago