Early Detection of Tumor Relapse in Triple-Negative Breast Cancer
Abstract
Cancer mortality among African American (AA) women with triple-negative breast cancer (TNBC) remains disparately high in this country. However, three decades of intensive research efforts and astronomical investments in breast cancer have yet to establish a curative measure to effectively control multidrug-resistant, relapsed, and metastatic mammary tumors. In this study, we will demonstrate the clinical utility of a panel of K-RAS?SIAH pathway-based prognostic protein biomarkers to stratify TNBC partial responders with residual cancer burdens (RCB), predict chemoresistance and early relapse, and develop an innovative and potent anti-TNBC strategy. The Hampton Roads area of Virginia has the highest TNBC mortality and morbidity rates in the United States. In a cohort of 700 TNBC patients, we have found African American women to be at much higher rates of late-stage presentation, multi-drug resistance, early tumor relapse, and mortality than White American (WA) patients. To tackle this issue, we have recruited three world-class leading physician scientists: Harry Bear, M.D., Ph.D. (Chair, Division of Surgical Oncology, and Director, the Breast Health Center, Virginia Commonwealth University), Emanuel F. Petricoin, Ph.D. (University Professor and Co-Director, Center for Applied Proteomics and Molecular Medicine, George Mason University), and Richard Hoefer, M.D., FACS (Medical Director, Sentara Cancer Network), who will guide us to advance this large-scale TNBC validation project. Dr. Petricoin and Dr. Wulfkuhle will help us to conduct groundbreaking, broad-scale "multi-Omics"-based molecular profiling of multidrug-resistant and high-grade TNBC tumor subtypes in the hopes of identifying new actionable targets for life-saving interventions. Ultimately, we hope that our practical findings (a prognostic biomarker panel and a new targeted anti-TNBC therapy) will translate into an improved stratification of TNBC partial responders, precise prediction of tumor relapse and remission, and development of innovative lifesaving strategies to eradicate multidrug-resistant and incurable TNBC tumors in the future. Innovation: Multidrug-resistant and high-grade TNBC is a genetically diverse, highly heterogeneous, and rapidly evolving disease that challenges our ability to individualize oncology and optimize precision medicine. We hypothesize that K-RAS?SIAH pathway activation is a major TNBC driver and that SIAH is a key TNBC vulnerability. Persistent K-RAS?SIAH?EGFR pathway activation endows these TNBC tumor cells with therapy resistance and increases the risk of metastasis and early relapse. To address these unmet needs, we propose three specific aims. In a retrospective study of 400 stage II and III TNBC patients (Aim 1) and a prospective study of 300 stage II and III TNBC patients (Aim 2), we will determine whether therapy-induced reduction in SIAH expression can be used to detect treatment disparities, quantify therapeutic efficacy, identify chemo-refractory tumor clones, and predict tumor relapse and TNBC survival. As SIAH is a logical anti-TNBC target, we will also assess the utility of an anti-SIAH-based strategy with respect to K-RAS?SIAH?EGFR pathway blockade, and the prevention of multidrug-resistant and incurable TNBC tumor growth in a "xenopatient" mouse model (Aim 3). These studies constitute an out-of-the-box strategy with the potential to guide treatment options and improve the survival of women with multidrug-resistant and metastatic TNBC. Rationale and Logic: Normal K-RAS/SIAH signaling pathway activation is indispensable for proper cell-cell communication, cell proliferation, and tissue homeostasis in multicellular organisms. However, abnormal K-RAS/SIAH pathway activation is highly prevalent in TNBC and may confer rampant chemoresistance to these high-risk mammary tumors. Like a jammed accelerator pedal that is stuck on the acceleration position in a race car, the unchecked activation of K-RAS/SIAH pa
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 05, 2019
- Source ID
- W81XWH1910054XX0
Entities
People
- Amy H Tang
Organizations
- Eastern Virginia Medical School
- United States Army