Biomarkers of vincristine-induced peripheral neuropathy

长春新碱是最常用的抗癌药物之一;但关于长春新碱的分布和最佳剂量知之甚少，这可能导致负面的临床结果，如药物过量引起的严重副作用或亚治疗剂量引起的疗效缺乏。阿曲斯汀与高度可变的累积剂量依赖性周围神经病变（PN）相关。当发生重度PN时，必须降低长春新碱剂量，以避免禁用PN。然而，长春新碱剂量降低可能导致亚治疗药物暴露，从而影响疗效。我们组的儿科数据表明，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，1）年轻CYP3A5表达者长春新碱代谢最快，2）快速长春新碱代谢与较轻的神经病变相关。虽然我们对长春新碱在ALL儿童中的相关知识不断增长，但在美国和发展中国家，长春新碱用于治疗超过50%的儿科癌症;我们在 尚未在这些其他儿科人群中对ALL儿童进行研究。该项目将使用一系列创新工具，以我们与长春新碱诱导PN（VIPN）相关的丰富知识基础为基础，实现我们在全球范围内优化长春新碱给药的目标。我们的总体假设是，一组集中的生物标志物（包括靶向长春花生物碱途径基因组学、PK和临床）最能预测VIPN。在这个项目中，我们将研究一组集中的生殖细胞基因组变异体在长春花生物碱药理学途径和长春新碱神经病变和药代动力学在两个儿童人群之间的关联。我们还建议使用基因分型的儿童和成人肝微粒体库仔细评价年龄和CYP3A5基因型对长春新碱代谢的影响。我们的生物统计学和建模核心将使用这些数据沿着我们现有的ALL儿童数据集，以开发一个更有依据的儿童长春新碱神经病变药理学预测模型，作为优化儿科长春新碱剂量的建议工具。

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.