Role of Angiotensin II-Mediated KLF4 Regulation in Gastric Cancer Metastasis
Abstract
The proposed research project will address the Fiscal Year 2019 (FY19) Peer Reviewed Cancer Research Programs (PRCRP) Topic Area “Stomach Cancer.” Stomach cancer (SC) or Gastric cancer (GC) is one of the most common and deadliest malignancies. According to the American Cancer Society (ACS), the estimated number of annual new diagnoses and mortality for GC in 2019 will be 27,510 and 11,140 respectively. According to ACS , the 5-year relative survival rates for patients with early localized stages of the disease is 68%. However, the 5-year relative survival rate decreases to 5% in advanced stages when the cancer cells spread to other parts of the body. Unfortunately, GC is often diagnosed at advanced stages when patients do not respond well to currently available therapies and therefore, ultimately die. Thus, identification of new and novel factors in these patients holds the key to the development of newer effective targeted therapy based on the principles of cancer biology. Our findings indicate that angiotensin II, a peptide-based hormone also secreted locally by the stomach, and its receptor angiotensin II receptor type 1 show significantly higher expressions in metastatic GC tissues ( human and also in experimental mouse GC models) compared to normal comparable stomach tissues. We therefore propose to study the in-depth role of this peptide hormone and its receptor in the metastatic progression of GC. Ultimate applicability of the research: On completion, our study may thus identify a new endogenous regulator (angiotensin II) of metastatic GC progression and establish drugs targeting angiotensin II receptor type 1 (receptor blockers) as agents for the treatment of advanced GC. These drugs can be used alone or in combination with existing therapies. Such blockers (angiotensin receptor blockers or ARBs) are already in clinical use for treatment of hypertension and renal disorders for many years, and the toxicity profile of these agents is also well established. Furthermore, and importantly, such blockers are much cheaper in comparison to the recent drugs available for treatment of GC in the clinics. Taken together, as our proposal aims to identify new roles of established drugs, any positive findings from this proposal can be rapidly translated to the clinics as clinical trials in order to determine the efficacy of angiotensin receptor blockers for the treatment of advanced gastric cancer. Repurposed drugs are generally approved in much shorter timeframes compared to the drugs that are developed de novo (1-3 years for clinical trials). FY19 PRCRP Military Health Focus Area: This study thus focuses on the FY19 PRCRP Military Health Focus Area “Treatment, and/or Survivorship.” SC is a common type of cancer and active military personnel and Veterans are high risk of developing SC in their lifetime due to their exposure to infectious agents (H.Pylori) during their deployment in countries where H. Pylori infection is prevalent. As GC is often diagnosed at later stages when the cancer cells have already spread to distant organs, which limits their treatment, any new treatment that would help in treatment of advanced disease will improve patient outcome both among general public as well as among military personnel.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010618
Entities
People
- Debanjan Chakroborty
Organizations
- Ohio State University
- United States Army