Targeting Drivers of Aggressive Triple-Negative Breast Cancer in African Americans
Abstract
Can we identify what drives breast cancer growth and determine how to stop it? This question has remained at the top of the list for many clinicians, researchers, and patients. This is especially true for triple-negative breast cancer (TNBC), an overly aggressive breast cancer subtype that disproportionately affects African American women. 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 aggressively growing tumors that readily metastasize. Recent next-generation sequencing studies have confirmed that TP53 mutations are the most frequent alterations in breast carcinomas, occurring in all subtypes of human breast cancer at varying rates. TP53 mutations are the only genetic correlate with poor clinical prognosis in TNBC. What makes TP53 mutations so deadly in TNBC? Our exciting new combined published and preliminary findings indicate that three tumor suppressors appear to be lost in the most aggressively growing forms of TNBC and were observed mostly in African American women. These tumors lack p53 along with the ARF and INK4A tumor suppressors (ARF and INK4A are encoded at the CDKN2A gene locus). Loss of all three suppressors results in the abnormal stimulation of JAK1 and CDK4 oncogenic kinases. When activated in concert, these two kinases are incredibly potent at stimulating tumor growth and metastasis. Thus, we believe that we have uncovered the genetic context for the most aggressive forms of TNBC. We hypothesize that TP53 and CDKN2A loss leads to aberrant JAK1 and CDK4 activities that serve as drivers for growth and metastasis that might be therapeutically targeted. To test this hypothesis, we propose to establish a repertoire of biological reagents and model systems that will act as a testing ground for new and available therapeutics. Our experiments will cover both in vitro and in vivo aspects of growth and metastasis using established human breast cancer cells, primary mouse mammary epithelial cells, and patient-derived TNBC tumor xenografts. Our goal is to effectively mimic the aggressive forms of TNBC seen in African American women and determine whether these tumors are sensitive to currently available drugs (itacitinib and palbociclib) that inhibit the activities of JAK1 and CDK4 kinases. The novelty of our approach lies in both our ability to accurately model this aggressive African American TNBC and in combining unique kinase inhibitors that target the true drivers of this tumor growth. Our combined expertise in tumor suppressors and oncogenes along with our unlimited access to the Human-in-Mouse Xenograft Core at Washington University gives us tremendous leverage in successfully obtaining large amounts of patient tumors to perform our in vivo analysis. We have recruited key collaborators to insure that we perform high-risk, yet sound experiments that are the most relevant to current breast cancer patients. Identification of required signaling components in aggressive TP53/CDKN2A mutant TNBC will lead to the evaluation of novel drug combinations targeting the key kinase drivers responsible for TNBC in African American women. How fast can we get there? The identification of JAK1 and CDK4 as key drivers of tumor growth suggests that therapeutic intervention is well within reach.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810026
Entities
People
- Cynthia Ma
Organizations
- United States Army
- Washington University in St. Louis