Identification of genetic predictors of bevacizumab induced hypertension

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 DESCRIPTION (provided by applicant): 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.