Date of Graduation
5-2015
Document Type
Dissertation (PhD)
Program Affiliation
Cell and Regulatory Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Heinrich Taegtmeyer, M.D. D.Phil
Committee Member
Diane Bick, Ph.D.
Committee Member
Mark Entman, M.D.
Committee Member
Hui-Kuan Lin, Ph.D.
Committee Member
David Moore, Ph.D.
Abstract
Cardiac dysfunction is one of the largest obstacles to effective cancer treatment. Not only do a growing number of cancer patients have significant cardiovascular risk factors at the time of diagnosis, but a number of targeted therapies can themselves cause cardiac dysfunction. These newer treatment options are also increasingly effective, placing a growing emphasis on post-cancer quality of life. In some instances, a patient may outlive his or her cancer only to succumb to heart failure in as little as five years. One such targeted therapy is the small molecular receptor tyrosine kinase sunitinib. Sunitinib was developed in the early 2000’s as part of a wave of antiangiogenic drugs that target the vascular endothelial growth factor receptors and platelet-derived growth factor receptors. Unfortunately, up to 47% of patients treated with sunitinib develop severe hypertension and approximately 20% develop cardiac dysfunction. The aim of my dissertation is therefore twofold: First, to identify the mechanism of sunitinib-induced cardiotoxicity in order to develop strategies to prevent clinical cardiotoxicity and, secondly, to use this mechanistic insight as a discovery platform to identify new targets for the treatment of human heart failure. My work led to the discovery that coronary microvascular pericytes are a primary target of sunitinib. Furthermore, co-treatment with thalidomide can protect from sunitinib-induced cardiac dysfunction without altering the antitumor effect of the drug. Examination of sunitinib-induced metabolic changes revealed that sunitinib treatment leads to a profound increase in glucose uptake in the heart and induction of the M2 isoform of pyruvate kinase. Collectively, my work suggests that vessel normalization and the Warburg Effect may be novel targets for the treatment of human heart failure.
Keywords
heart failure, PKM2, Warburg Effect