Biomarkers of vincristine-induced peripheral neuropathy

长春新碱是最常用的抗癌药物之一；但对于长春新碱的处置和最佳剂量知之甚少，这可能导致负面的临床结果，如药物过量导致的严重副作用或亚治疗剂量导致的疗效不足。长春新碱与高度可变累积剂量依赖性周围神经病变（PN）相关。当发生严重的PN时，必须减少长春新碱的剂量，以避免使PN失能。然而，减少长春新碱剂量可能导致亚治疗性药物暴露，从而影响疗效。我们小组的儿科数据表明，急性淋巴细胞白血病（ALL）患儿的CYP3A5基因型、PN、患者年龄和长春新碱代谢之间存在联系，1)年轻的CYP3A5表达者长春新碱代谢最快，2)快速的长春新碱代谢与较轻的神经病变相关。虽然我们对ALL儿童中长春新碱的相关知识体系正在增长，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；我们对长春新碱的了解

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.