Targeting an Innate Immune Signaling Pathway to Treat TNBC
Abstract
Can we identify why some breast cancers become life-threatening metastasis? Can we identify what drives cancer growth and determine how to stop it. These questions have remained at the top of the list for many clinicians, researchers, and patients. Metastasis of cancer cells from the breast to distal target organs is the single-most important cause of mortality in women with breast cancer. One of the most challenging aspects of eradicating breast cancer and increasing the survival rates of women with breast cancer is the prevention and/or treatment of metastasis. Triple-negative breast cancer (TNBC) remains a challenge to clinicians, laboratory investigators, and patients due to its disproportionate number of breast cancer deaths and its lack of an established therapeutic target. Numerous studies have identified potential novel mutational gene targets in TNBC, but single-agent therapeutics have lacked substantial impact in TNBC. More recently, scientists have begun to study ways to activate our own immune system to fight off cancer. These immune checkpoint inhibitors gained significant clinical traction in breast cancer. Unfortunately, initial promising results have been subsequently overshadowed with failures, particularly in TNBC. In other solid human tumors, the efficacy of immune checkpoint therapies appeared to be enhanced by stimulating our own immune cells into entering the tumor microenvironment in larger numbers to fight the tumor cells. We appear to have found a way to do this effectively in breast cancer by stimulating a pathway controlled by the RIG-I protein. We have discovered that an innate immunity pathway controlled by RIG-I is elevated in a subset of human TNBC. We hypothesize that this RIG-I pathway can be exploited to increase tumor immune cell infiltration and immune recognition of human TNBC. In order to address this hypothesis, we propose two specific aims: (1) To determine whether there are actionable/druggable components in the RIG-I pathway that prevent TNBC tumor growth and metastasis. (2) To determine whether the RIG-I pathway can be exploited in TNBC to render tumors sensitive to immune-based therapies. Our combined expertise and our unlimited access to human TNBC tumor samples at Washington University gives us tremendous leverage in successfully obtaining large amounts of breast cancer patient tumors to perform our experiments. Importantly RIG-I agonists and anti-PD-L1 immune checkpoint inhibitors have already been shown to be safe in clinical trials. This precludes us from having to perform initial toxicity screens for new drugs. This bodes extremely well for the immediate translation of our findings into TNBC patients within the 3-year time frame of this award. Our studies would point towards the use of agonists that stimulate immune infiltration as a way to increase the efficacy of current immune checkpoint therapies. Moreover, our work would help define and identify TNBC patients that have interferon sensitive gene signatures as being more apt to respond to our novel RIG-I agonist and anti-PD-L1 combination therapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110466
Entities
People
- Jason D Weber
Organizations
- United States Army
- Washington University in St. Louis