BLRD Research Career Scientist Award Application

John D Dingell Va Medical Center, Detroit MI

Investigators

Linked publications & trials

Abstract

Inflammation is the body's attempt at self-protection to remove harmful stimuli and begin the healing process. Chronic inflammation can eventually cause several diseases and conditions, including cancers, rheumatoid arthritis, atherosclerosis, and plays a role in heart disease. The overarching goals of nominee’s research involve elucidating molecular underpinnings of cell growth/survival and death/apoptosis with particular reference to cancer, atheroscleroscosis, and cardiovascular hypertension. The American Cancer Society estimates highest percent of new cases and mortality resulting from lung and breast cancers in females, while prostate and lung cancers account for highest percentage of new cases and associated mortality among men. Overall incidence rates and mortality due to lung and breast cancers have decreased over last decade partly due to advances in diagnosis and therapeutics, particularly targeted therapeutics for a number of cancers including the non-small cell lung cancers (NSCLCs). However, adaptive genetic alterations and mutations in cancers contribute to therapy failures and relapses in clinic occur that often result in emergence of resistant, hard to treat disease, and warrant development of new therapeutic strategies to overcome drug resistance and improve therapeutic outcomes. By utilizing a functional gene-knockout approach the nominee identified a novel, apoptosis inducing protein termed CARP-1/CCAR1 (J. Biol. Chem. 278: 33422-33435, 2003). CARP-1 regulates apoptosis signaling induced by diverse therapeutics such as Adriamycin, Etoposide, and Gefitinib (Oncotarget 6(9): 6499- 510, 2015). Following CARP-1 discovery, the nominee conducted a chemical-biological approach to identify novel small molecule CARP-1 Functional Mimetic (CFMs) compounds (J. Biol. Chem. 286 (44): 38000-38017, 2011). CFMs inhibit growth of therapy-resistant triple-negative breast cancers (TNBC) and non-small cell lung cancers (NSCLCs) in part by inducing CARP-1-dependent apoptosis (Oncotarget, 7(45): 73370–73388, 2016; 8(62):104928-104945, 2017; 9(51): 29680-29697, 2018). During RCS funding, nominee made a fundamental observation that CARP-1 interacts with NF-κB kinase subunit gamma (IKKγ). This interaction functions to activate NF-κB-dependent cell survival and growth in genotoxic chemotherapy-treated cancer cells (J. Biol. Chem. 295: 3532-3552, 2020). Targeting of IKKγ-CARP-1 binding prevents therapy-induced NF-κB activation. On the basis of this finding nominee discovered new compounds, termed selective NF-κB inhibitors (SNIs), that target IKKγ-CARP-1 binding to attenuate therapy-induced survival pathways and enhance efficacy of cisplatin in preclinical tumor models of breast and renal cancers. Given that cisplatin is widely used anti-cancer therapeutic in BRCA-mutant breast, non-small cell lung, and kidney cancers, SNI compounds will provide a novel avenue to improve chemotherapy efficacy and attenuate emergence of drug-resistant cancers. The nominee’s long-term goal is to elucidate molecular mechanisms of therapy resistance in TNBC and NSCLCs, and utilize this knowledge to develop novel, safer and effective anti-cancer modalities. In this context CFMs and SNIs or their derivatives are anticipated to facilitate development of strategies for effective treatment of TNBC, NSCLCs, and other cancers in the VA healthcare system and beyond. Prevalence of atherosclerotic reno-vascular hypertension is rising. Renal artery stenosis occurs in 28% of veterans undergoing cardiac catheterization with a greater than 3-fold risk in those over age 65. There is an alarming burden of cardiovascular and renal morbidity and mortality with attendant increases in direct medical costs, loss of productivity and quality of life in our Veterans with hypertension. The nominee continues to have a productive collaboration with Detroit VA clinician-scientist to study the molecular and behavioral mechanisms of the angiotensin-endothelin signaling in Reno-vascular model. In RCS funding period, nominee served as a co- investigator of the two VA funded Merit applications that investigated mechanisms of reno-vascular hypertension.