The prophylactic role of renin-angiotensin system antagonism in the prevention of Bevacizumab and Sunitinib mediated cardiotoxicity

Abstract

Cardio-Oncology is a novel discipline that focuses on the prevention, diagnosis, and management of cancer patients who are at risk of developing cardiovascular complications as a result of their cancer treatment. Two types of targeted therapy currently in use for colorectal (CRC) and renal cell cancer (RCC), respectively, are the monoclonal antibody Bevacizumab (BVZ; Avastin) and the tyrosine kinase inhibitor Sunitinib (SNT; Sutent). An unexpected side effect of the use of these two anti-cancer drugs is the increased risk of cardiotoxicity. Serial monitoring of left ventricular ejection fraction (LVEF) using noninvasive cardiac imaging is the single most important clinical diagnostic tool in the recognition of cardiac dysfunction in cancer patients. Once heart failure develops in the setting of a reduced LVEF, however, irreversible cardiac injury may potentially occur. Although heart failure medications including renin-angiotensin system (RAS) antagonists are commonly used after LV systolic dysfunction develops in the CRC and RCC population, it raises the question of whether BVZ and SNT mediated cardiotoxicity can be prevented altogether. The two specific aims of our BSc Med research proposal include: Aim 1: To evaluate whether early pharmacological inhibition of oxidative stress (OS) by RAS antagonists will attenuate the cardiotoxic side effects of BVZ or SNT in a chronic in vivo murine model. Aim 2: To elucidate potential mechanisms for the cardioprotective effects of RAS antagonism by characterizing the downstream levels of MAPKs and TGF-β1/SMADs in this model.