Pharmacogenetic Determinants of Vincristine Toxicity and Response

长春新碱毒性和反应的药物遗传学决定因素

基本信息

批准号：
8016176
负责人：
JAMIE L RENBARGER
金额：
$ 43.8万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8016176
关键词：
ABCB1 gene Acute Lymphocytic Leukemia Address Adult Adverse effects Affect Antineoplastic Agents B-Cell Acute Lymphoblastic Leukemia Biological Assay CYP3A4 gene CYP3A5 gene Candidate Disease Gene Child Childhood Childhood Acute Lymphocytic Leukemia Clinical Clinical Oncology Clinical Pharmacology Clinical Trials Code DNA Data Disease Dose Dose-Limiting Drug Exposure Drug Kinetics Drug toxicity Enrollment Enzymes Evaluation Genes Genetic Genetic Determinism Genetic Polymorphism Genome Genomics Genotype Goals Health Human Genome In Vitro Individual Individual Differences Institution Knowledge Lead Literature Malignant Childhood Neoplasm Malignant Neoplasms Measurement Measures Metabolism Multicenter Trials Neuropathy Other Genetics Outcome Parents Pathway interactions Patients Pediatric Oncology Group Peripheral Nervous System Diseases Pharmaceutical Preparations Pharmacogenetics Phenotype Population Publishing Reporting Research Risk Sampling Series Severities Signal Pathway Source Terminology Testing Therapeutic Time Toxic effect Treatment Efficacy Validation Variant Vinca Alkaloids Vincristine base catalyst chemotherapy chemotherapy induced neuropathy clinical practice cohort effective therapy experience genetic association genetic variant genome wide association study genome-wide improved innovation insight knowledge base neurotoxicity novel novel strategies painful neuropathy prospective receptor response tool treatment trial

项目摘要

DESCRIPTION (provided by applicant): Vincristine is active against a wide variety of malignancies and has been shown to substantially improve outcomes. Although vincristine is among the most commonly used anticancer agents, little is known about optimal therapeutic dosing and it is widely recognized that improper dosing can lead to serious side effects or lack of efficacy. Vincristine is associated with highly variable neurotoxicity that often necessitates dose reductions, thereby compromising efficacy. Recently published data indicate that vincristine pharmacokinetics may be associated with long-term outcomes in children with acute lymphoblastic leukemia (ALL). Two enzymes (CYP3A4 and 3A5) metabolize vincristine; but CYP3A5 is 10-times more efficient as a catalyst of vincristine metabolism. Severity of neurotoxicity may be directly related to an individual patient's vincristine exposure. It may be possible to optimize vincristine dosing based on knowledge of genetic polymorphisms responsible for vincristine metabolism that alter drug exposure and the risk of neurotoxicity. The long-range goal of this research is to optimize the use of this critically important drug. The objective of this proposal is to assess whether candidate gene polymorphisms or other less obvious genetic variants identified using a genome wide approach are predictive of vincristine neurotoxicity. The central hypothesis is that germline genetic polymorphisms are associated with vincristine toxicity, pharmacokinetics, and efficacy. The first and second aims are to evaluate the association of pharmacogenetic polymorphisms in candidate genes and in the vinca alkaloid pharmacologic pathway, respectively, with vincristine toxicity, efficacy, and pharmacokinetics. Given that other genes may be involved and genome-wide approaches may miss important genetic associations, we propose a candidate pathway approach as aim 2. These aims will involve enrollment of a single cohort of 175 children with precursor B cell ALL to a multicenter prospective clinical trial. DNA and pharmacokinetics will be collected and patients will be followed throughout their treatment for evidence of vincristine neurotoxicity using the standard NCI Common Terminology Criteria as well as more specific and sensitive neuropathy assessment tools (validated in adults) that we will attempt to validate in children. Aim 3 is to test for the association of multiple genetic polymorphisms with vincristine toxicity using a genome wide approach in children with ALL enrolled to completed cooperative group trials in which whole genome arrays have been completed. A second phenotyped population (175 children enrolled on multicenter trial above and 140 children enrolled to a nearly completed trial of pharmacogenetics of vincristine neurotoxicity) will be used as a validation cohort. We expect that this research will provide important new information regarding the association of genetic variables and vincristine toxicity, efficacy, and pharmacokinetics. The results will be significant because they address an important gap in knowledge and will provide the basis for subsequent studies aimed at optimization of vincristine dosing for individual patients in treating curable pediatric diseases.

描述（由申请人提供）：长春新碱对各种恶性肿瘤有效，并已证明可以大大改善结果。尽管长春新碱是最常用的抗癌药之一，但对最佳治疗剂量的了解鲜为人知，并且广泛认识到，不当剂量会导致严重的副作用或缺乏疗效。长春新碱与高度可变的神经毒性相关，通常需要降低剂量，从而损害疗效。最近发布的数据表明，长春蛋白药代动力学可能与急性淋巴细胞白血病儿童的长期结局有关（ALL）。两种酶（CYP3A4和3A5）代谢长春新碱；但是CYP3A5作为长春新碱代谢的催化剂的效率更高10倍。神经毒性的严重程度可能与单个患者的长春新碱暴露直接相关。可能会根据对遗传多态性的知识来优化vincristine剂量，从而改变药物暴露和神经毒性的风险。这项研究的远程目标是优化这种至关重要的药物的使用。该提案的目的是评估候选基因多态性或其他不太明显的遗传变异剂是使用基因组范围的方法鉴定的，可以预测vincristine神经毒性。中心假设是种系遗传多态性与长春新碱的毒性，药代动力学和功效有关。第一个和第二目的是评估候选基因和VINCA生物碱药理学途径中药物遗传学多态性的关联，以及vincristine的毒性，功效和药代动力学的关联。鉴于可能涉及其他基因，并且全基因组方法可能会错过重要的遗传关联，因此我们提出了作为AIM 2的候选途径方法。这些目标将涉及将175名具有前体B细胞的175名同类群体入学到一项多中心前瞻性临床试验中。将收集DNA和药代动力学，并在整个治疗过程中遵循患者，以证明使用标准NCI常见术语标准以及更具体和敏感的神经病评估工具（在成人中进行了验证），我们将试图在儿童中验证这一点。 AIM 3是使用基因组广泛的方法来测试多种遗传多态性与vincristine毒性的关联。第二次表型人口（175名儿童参加了上述多中心试验，140名儿童招收了Vincristine神经毒性的几乎完成的药物遗传学试验）将用作验证队列。我们预计这项研究将提供有关遗传变量和长春新碱毒性，功效和药代动力学的关联的重要新信息。结果将很大，因为它们解决了知识的重要差距，并将为旨在优化单个患者在治疗可治愈的儿科疾病中优化长春新碱给药的研究提供基础。