UCSF

Bevacizumab is a vascular endothelial growth factor-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of several types of cancer. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy and lead to other cardiovascular complications. The factors that contribute to interindividual variability in blood pressure response to bevacizumab treatment are not well understood. To identify novel mechanisms of bevacizumab-induced hypertension, the research in this dissertation explored genetic variation associated with the toxicity. A sequencing analysis of whole exomes and candidate gene regulatory regions identified a genomic region between SLC29A1 and HSP90AB1 containing several variants associated with hypertension in colorectal cancer patients with extreme toxicity phenotypes. Functional experiments in human endothelial cells provide evidence that variation in SLC29A1 (ENT1) expression is associated with altered adenosine signaling that modulates the synthesis of vasodilatory molecules during bevacizumab treatment. These results suggest that increased basal expression of SLC29A1 and low extracellular adenosine levels may sensitive patients to a rise in blood pressure during bevacizumab exposure. Additionally, a genome-wide association study of a larger, independent cohort of breast cancer patients identified variants associated with cumulative bevacizumab dose at the first occurrence of hypertension. Several of these SNPs are located within or near genes of biological interest (MSH6, SDC4, ASB5, SMYD5) and may highlight additional mechanisms important in the pathogenesis of the toxicity. Collectively, the studies in this dissertation identified novel genetic loci that potentially modify the risk of developing bevacizumab-induced hypertension. The results of this research will advance understanding of the biological mechanism of this adverse drug reaction and should be considered in the future use and development of angiogenesis inhibitors.