Identification of genetic predictors of bevacizumab induced hypertension

贝伐珠单抗诱发高血压的遗传预测因子的鉴定

基本信息

批准号：
8978933
负责人：
Megan Stephanie Li
金额：
$ 3.67万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8978933
关键词：
Address Adverse event Angiogenesis Inhibitors Antibodies Antihypertensive Agents Antineoplastic Agents Architecture Binding Bioinformatics Biological Assay Biological Markers Blood Pressure Blood Vessels Cancer Patient Candidate Disease Gene Cell physiology Clinical Research Clinical Trials Coculture Techniques Complex Development Drug toxicity Endothelial Cells Gene Expression Genes Genetic Genetic Markers Genome Genotype Hypertension In Vitro Incidence Individual Literature Mediating Molecular Genetics Non-Malignant Nucleic Acid Regulatory Sequences Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Play Predisposing Factor Predisposition Reaction Regulation Relative (related person)Reporting Research Research Design Risk Role Severities Signal Transduction Single Nucleotide Polymorphism Small Interfering RNA Smooth Muscle Myocytes System Therapeutic Therapeutic antibodies Toxic effect Variant Vascular Endothelial Growth Factor A Vascular resistance Vasodilation angiogenesis bevacizumab cancer type cohort cytotoxic early onset exome exome sequencing experience familial hypertension genetic approach genetic predictors genetic variant intercellular communication neoplastic cell novel overexpression public health relevance rare variant receptor response tool tumor tumor microenvironment vasoconstriction

项目摘要

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.

描述（由申请人提供）：贝伐单抗是一种治疗性抗 VEGF 抗体，被批准用于治疗多种类型的癌症。在大多数患者中，在贝伐单抗治疗期间经常观察到血压升高。使用标准抗高血压药物；然而，5-18% 接受贝伐单抗治疗的患者很快会出现严重的高血压，并且必须停止原本可能有益的治疗，尽管贝伐单抗被广泛使用，但其机制仍然存在。其导致 HTN 的原因以及导致患者发生这种药物不良反应的因素尚不清楚。确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，从而可能导致这种药物不良反应的风险。更为复杂，包括其他基因的变异以及罕见变异，本研究追查存在可预测贝伐珠单抗诱导的高血压的其他遗传变异，并且这些变异改变了贝伐珠单抗期间血管张力的调节。本研究的具体目的是：（1a）通过对接受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异，（1b）鉴定含有过量与药物毒性相关的罕见变异的基因。通过对发生严重、早发性贝伐单抗诱导的 HTN 的患者进行全外显子组测序来确定药物毒性，以及 (2) 确定与贝伐单抗诱导的 HTN 相关的变异是否影响 VEGF 刺激的血管舒张目标 2 将使用分子和遗传学方法，利用体外共培养系统来研究血管细胞信号传导和功能的变化。将促进对遗传变异如何影响血管生成抑制剂的作用和药物引起的高血压发病机制的理解此外，确定这种毒性的遗传预测因素可以帮助为癌症患者选择适当的治疗方法。支持理解和开发治疗贝伐单抗诱导的高血压的新策略。