Bevacizumab is a therapeutic anti-VEGF antibody approved for the treatment of several types of cancer. The development of hypertension (HTN) is frequently observed during bevacizumab treatment. In most patients, the blood pressure increase can be controlled with standard anti-hypertensive medications; however, 5-18% of patients given bevacizumab quickly develop severe HTN and must discontinue treatment that may otherwise be beneficial. Despite the wide usage of bevacizumab, the mechanism by which it causes HTN is not well understood nor are the factors that predispose patients to this adverse drug reaction. In searching for genetic biomarkers of this toxicity, previous clinical studies have identified several VEGF pathway and HTN- susceptibility SNPs associated with incidence of bevacizumab-induced HTN. However, limitations of these study designs warrant more extensive research in larger cohorts and across the genome. The genetic architecture contributing to the risk of this adverse drug reaction may be more complex and include variation in other genes as well as rare variants. This study hypothesizes that there are additional genetic variants that are predictive of bevacizumab-induced HTN and that these variants alter the regulation of vascular tone during bevacizumab treatment.
The specific aims of this study are to: (1a) Identify common variants associated with the drug toxicity by performing a candidate gene association study on bevacizumab-treated patients, (1b) Identify genes containing an overabundance of rare variants that are associated with the drug toxicity through whole-exome sequencing of patients who develop severe, early-onset bevacizumab-induced HTN, and (2) Determine whether variants associated with bevacizumab-induced HTN influence VEGF-stimulated vasodilation following bevacizumab treatment.
Aim 2 will use molecular and genetic approaches to study changes in vascular cell signaling and function using an in vitro co-culture system. The results of this study will advance understanding of how genetic variability influences the action of angiogenesis inhibitors and the pathogenesis of drug-induced HTN. Furthermore, identifying genetic predictors of this toxicity could aid in the selection of appropriate treatment for cancer patients and support the understanding and development of new strategies to treat bevacizumab-induced HTN.

Public Health Relevance

Bevacizumab is a widely-used cancer drug that causes severe hypertension in certain patients, but the mechanism and factors that predispose individuals to this toxicity risk are not well understood. This project aims to identify genetic variants that are predictive of this adverse event and to determine how these variants alter the regulation of vascular tone during bevacizumab treatment. The results of this study will advance understanding of how genetic variability influences the action of angiogenesis inhibitors and the pathogenesis of drug-induced hypertension.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31GM113350-02
Application #
9113354
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Barski, Oleg
Project Start
2015-09-01
Project End
2017-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118