Pharmacogenetic Determinants of Vincristine Toxicity and Response

描述（由申请人提供）：长春新碱对多种恶性肿瘤具有活性，并已被证明可显著改善预后。尽管长春新碱是最常用的抗癌药物之一，但人们对最佳治疗剂量知之甚少，而且人们普遍认为，不适当的剂量会导致严重的副作用或缺乏疗效。长春新碱具有高度可变的神经毒性，通常需要减少剂量，从而影响疗效。最近发表的数据表明，长春新碱的药代动力学可能与急性淋巴细胞白血病（ALL）患儿的长期预后有关。两种酶（CYP3A4和3A5）代谢长春新碱；但CYP3A5作为长春新碱代谢催化剂的效率是它的10倍。神经毒性的严重程度可能与个体患者的长春新碱暴露有直接关系。基于对长春新碱代谢的遗传多态性的了解，有可能优化长春新碱的剂量，从而改变药物暴露和神经毒性的风险。这项研究的长期目标是优化这种至关重要的药物的使用。本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是否可以预测长春新碱神经毒性。中心假设是种系遗传多态性与长春新碱毒性、药代动力学和疗效有关。第一个和第二个目的是分别评估候选基因和长春花生物碱药理学途径中药物遗传多态性与长春新碱毒性、疗效和药代动力学的关系。鉴于可能涉及其他基因，并且全基因组方法可能错过重要的遗传关联，我们提出了一种候选途径方法作为目标2。这些目标包括招募175名患有前体B细胞ALL的儿童进行多中心前瞻性临床试验。我们将收集DNA和药代动力学数据，并在整个治疗过程中对患者进行随访，使用标准的NCI通用术语标准以及更具体和敏感的神经病变评估工具（在成人中验证）来寻找长春新碱神经毒性的证据，我们将尝试在儿童中验证。目的3是使用全基因组方法测试ALL患儿多基因多态性与长春新碱毒性的关联，这些患儿已完成合作组试验，全基因组阵列已完成。第二个表型人群（175名儿童参加了以上多中心试验，140名儿童参加了一项即将完成的长春新碱神经毒性药物遗传学试验）将被用作验证队列。我们期望这项研究将提供有关遗传变量与长春新碱毒性、疗效和药代动力学相关性的重要新信息。这一结果具有重要意义，因为它们填补了知识上的一个重要空白，并将为后续研究提供基础，旨在优化长春新碱在治疗可治愈的儿科疾病中的个体化剂量。

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.