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 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 therapeutic modalities, 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 chemotherapeutics such as Adriamycin, Etoposide, and Gefitinib (reviewed by nominee in 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 diverse cancer cells including therapy-resistant triple-negative breast cancers (TNBC) and non-small cell lung cancers (NSCLCs) in part by binding with CARP-1, causing elevated levels of CARP-1 and apoptosis (Oncotarget, 2016, in press). The nominee?s long-term goal is to elucidate molecular mechanisms of therapy resistance in cellular models of resistant TNBC and NSCLCs, and utilize this knowledge to develop novel, safer and effective anti-cancer modalities. In this context CFMs or their derivatives are anticipated to have clinical utility, and could provide novel means to develop future strategies for effective treatment of TNBC, NSCLCs, and other cancers in the VA healthcare system and beyond. Hypertension is a major health issue in the U.S., and the prevalence of atheros clerotic 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. Nonetheless, 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 has a productive collaboration with Detroit VA clinician- scientist to study the molecular mechanisms of the hypertension. Since CARP-1 is also a co-activator of the signaling by the steroid-thyroid receptors (Molecular Cell 31: 510-519, 2008), and with the knowledge that mineralocorticoid receptor is known to play an important role in reno-vascular signaling, a potential overlap of CARP-1 functions in this model was envisioned. Moreover, the fact that anti-cancer chemotherapies often affect cardiac functions in patients, the nominee initiated this collaboration to study overlapping as well as specific, perhaps, novel aspects of the angiotensin-endothelin signaling in Reno-vascular model. Although this hypothesis has yet to tested, the nominee has thus far contributed in publication of an abstract in a national meeting and is serving as a co-investigator of the two current VA funded Merit applications that focus on investigating mechanisms of reno-vascular hypertension.
The nominee?s research investigates molecular mechanisms of disorders associated with chronic inflammation such as breast and lung cancers, and reno-vascular hypertension. These diseases are known to cause significant morbidity and mortality with attendant increases in direct medical costs, loss of productivity and quality of life in our veterans of all ages. The research projects are intended to elucidate mechanisms of drug resistance in human triple-negative breast (TNBC) and non-small cell lung cancers (NSCLC), and exploit this knowledge to design, synthesize and optimize nano-delivery of novel compounds that activate CARP-1 and apoptosis in nave and drug-resistant cancer cells. Both the CARP-1 and the novel compounds were discovered by the nominee through the VA supported Merit funds. The nominee is also productively collaborating with Detroit VA clinician to investigate mechanisms of reno-vascular hypertension, and supported (as co-investigator) by two, currently funded VA Merit proposals. Rishi - 1