Identification of genetic predictors of bevacizumab induced hypertension

 描述（由申请方提供）：贝伐珠单抗是一种治疗性抗VEGF抗体，获批用于治疗几种类型的癌症。在贝伐珠单抗治疗期间经常观察到高血压（HTN）的发生。在大多数患者中，血压升高可以用标准抗高血压药物控制;然而，5-18%给予贝伐珠单抗的患者迅速发展为重度HTN，必须停止治疗，否则可能是有益的。尽管贝伐珠单抗的广泛使用，但其引起HTN的机制尚不清楚，也不清楚使患者易患这种药物不良反应的因素。在寻找这种毒性的遗传生物标志物时，以前的临床研究 鉴定了与贝伐珠单抗诱导的HTN发生率相关的几种VEGF途径和HTN易感性SNP。然而，这些研究设计的局限性需要在更大的队列和整个基因组中进行更广泛的研究。导致这种药物不良反应风险的遗传结构可能更复杂，包括其他基因的变异以及罕见变异。本研究假设存在可预测贝伐珠单抗诱导HTN的其他遗传变异，并且这些变异改变了贝伐珠单抗治疗期间血管张力的调节。这项研究的具体目标是：（1a）通过对贝伐珠单抗治疗的患者进行候选基因关联研究来鉴定与药物毒性相关的常见变体，（1b）通过对发展严重的早发性贝伐珠单抗诱导的HTN的患者进行全外显子组测序来鉴定含有过量的与药物毒性相关的罕见变体的基因，和（2）确定与贝伐单抗诱导的HTN相关的变体是否影响贝伐单抗治疗后VEGF刺激的血管舒张。目标2将利用分子和遗传学方法研究血管细胞信号转导和功能的变化，使用体外共培养系统。本研究结果 将促进对遗传变异性如何影响血管生成抑制剂的作用和药物诱导的HTN的发病机制的理解。此外，确定这种毒性的遗传预测因子有助于为癌症患者选择适当的治疗方法 并支持理解和开发治疗贝伐珠单抗诱导的HTN的新策略。

 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.