Biomarkers of vincristine-induced peripheral neuropathy

长春新碱是最常用的抗癌药物之一；但人们对长春新碱的处置和最佳剂量知之甚少，这可能会导致负面的临床结果，如药物过量导致的严重副作用或亚治疗性剂量导致的无效。长春新碱与高度可变的累积剂量依赖性周围神经病(PN)相关。当出现严重的PN时，必须减少长春新碱的剂量，以避免使PN失效。然而，减少长春新碱的剂量可能会导致亚治疗性药物暴露，从而影响疗效。来自我们小组的儿科数据表明，在急性淋巴细胞白血病(ALL)儿童中，CYP3A5基因型、PN、患者年龄和长春新碱代谢之间存在联系，其中1)年轻时长春新碱代谢最快，2)长春新碱快速代谢与较轻的神经病变相关。虽然我们关于长春新碱在ALL儿童中的知识体系正在增长，长春新碱在美国和发展中国家都被用于治疗超过50%的儿童癌症；我们在 在这些其他儿科人群中，没有对ALL儿童进行调查。该项目将使用一系列创新工具来建立我们与长春新碱诱导的PN(VIPN)相关的大量知识库，以实现我们优化世界各地儿童长春新碱剂量的目标。我们的总体假设是，一组聚焦的生物标记物(包括靶向长春花碱途径基因组学、PK和临床)最能预测VIPN。在这个项目中，我们将在两个儿童群体中检验长春花碱生物碱药理途径中一组集中的生殖系基因组变异与长春新碱神经病变和药代动力学之间的联系。我们还建议使用一组分型的儿童和成人肝微粒体库，仔细评估年龄和CYP3A5基因对长春新碱代谢的影响。我们的生物统计和建模核心将使用这些数据以及我们来自ALL儿童的现有数据集，开发更知情的儿童长春新碱神经病变的药理学预测模型，作为为优化儿童长春新碱剂量提出建议的工具。

Vincristine is among the most commonly used anticancer agents; but little is known regarding vincristine's disposition and optimal dosing, which can lead to negative clinical outcomes such as serious side effects due to drug overdosing or lack of efficacy due to sub-therapeutic dosing. Vincristine is associated with highly variable cumulative dose-dependent peripheral neuropathy (PN). When severe PN occurs, the vincristine dosage must be decreased to avoid disabling PN. However, vincristine dose reductions may result in sub-therapeutic drug exposure, thereby compromising efficacy. Pediatric data from our group indicate links between CYP3A5 genotype, PN, patient age, and vincristine metabolism in children with acute lymphoblastic leukemia (ALL) with 1) young CYP3A5 expressers having the fastest vincristine metabolism and 2) fast vincristine metabolism being associated with less severe neuropathy. While our body of knowledge related to vincristine in children with ALL is growing, vincristine is used in the treatment of over 50% of pediatric cancers both in the U.S. and in developing countries; and the things we have learned about vincristine in children with ALL have not been investigated in these other pediatric populations. This project will use a series of innovative tools to build on our substantial knowledge base related to vincristine-induced PN (VIPN) toward achieving our goal of optimizing vincristine dosing for children throughout the world. Our overall hypothesis is that a focused panel of biomarkers (including targeted vinca alkaloid pathway genomics, PK, and clinical) best predicts VIPN. In this project, we will examine the association between a focused panel of germline genomic variants in the vinca alkaloid pharmacologic pathway and vincristine neuropathy and pharmacokinetics in two populations of children. We also propose to carefully evaluate the impact of age and CYP3A5 genotype on vincristine metabolism using a bank of genotyped pediatric and adult human liver microsomes. Our Biostatistics and Modeling Core will use these data along with our existing dataset from children with ALL to develop a more informed pharmacologic prediction model of vincristine neuropathy in children as a tool for making recommendations for optimized pediatric vincristine dosing.