Genetics-guided Individualization of Thiopurine Therapy

摘要 硫代嘌呤(例如，硫代嘌呤[MP])对血液系统恶性肿瘤(白血病和 和自身免疫性疾病(炎症性肠病[IBD])。在急性淋巴细胞白血病中 尤其是，要治愈这种癌症，每天长时间接触MP是必不可少的。然而， 硫脲类药物的治疗指数很窄，具有剂量限制的造血毒性，导致广泛的 发病率、治疗中断和可能的死亡率。因此，有巨大的临床益处。 预先识别有硫代嘌呤中毒风险的患者，并进行个体化治疗以减轻其影响。硫代嘌呤 毒性也受到遗传变异的高度影响，特别是TPMT基因的多态。 正如我们团队和其他人所发现的那样。最近，我们报道了NUDT15基因的一个新的变异，它导致了 其核苷酸二磷酸酶活性丧失，硫代谢物活性超标，急剧增加 MP诱导的细胞凋亡和患者的严重毒性(J Clin Onol 2015和未发表的初步报告) 结果)。 因为低活性的NUDT15等位基因改变了硫嘌呤的新陈代谢，我们假设我们可以 合理减少携带NUDT15变异的患者的硫代嘌呤剂量，并量身定制其暴露于 硫嘌呤活性代谢物TGTP达到与接受常规剂量的野生型患者相当的水平， 类似于TPMT引导的硫代嘌呤剂量减少的原理。为了检验这一假设，我们提出了三个假设 具体目标：1)全面识别与MP毒性相关的NUDT15和 TPMT ALL(N=1,028)，2)描述NUDT15和 描述NUDT15及其变体如何影响急性淋巴细胞白血病(N=1,550)儿童的硫代嘌呤倾向， TPMT 变体 患有多发性硬化症儿童的变异 关于它的功能，最后是3) TPMT 由此开发一种基于NUDT15/TPMT的MP剂量调整的药物遗传算法。 这些研究的成功完成很可能为硫代嘌呤建立一种新的精确医学范例 在毒性发生前主动个体化给药的治疗。我们相信，这一高度翻译的 该项目可能会对ALL的治疗产生立竿见影的影响，我们的发现很容易推断出来 对于非恶性疾病(例如IBD)的硫代嘌呤治疗，因此影响了大量患者。

Abstract Thiopurines (e.g., mercaptopurine [MP]) are highly effective against hematologic malignancies (leukemia and lymphoma) and autoimmune diseases (inflammatory bowel diseases [IBD]). In acute lymphoblastic leukemia (ALL) in particular, prolonged daily exposure to MP is indispensable for the cure of this cancer. However, thiopurines have narrow therapeutic indexes with dose-limiting hematopoietic toxicity that causes extensive morbidity, disruption of treatment, and possible mortality. Therefore, there is enormous clinical benefit from preemptively identifying patients at risk of thiopurine toxicity and individualizing therapy to mitigate it. Thiopurine toxicity is also highly influenced by inherited genetic variations, particularly polymorphisms in the TPMT gene as discovered by our group and others. Recently, we reported a novel variant in the NUDT15 gene that lead to its loss of nucleotide diphosphatase activity, excessive levels of active thiopurine metabolite, dramatic increase in MP-induced apoptosis and severe toxicity in patients (J Clin Oncol 2015 and unpublished preliminary results). Because the low activity NUDT15 allele alters the metabolism of thiopurines, we hypothesize that we can rationally reduce thiopurine dose in patients who inherit the NUDT15 variants and tailor their exposure to thiopurine active metabolite TGTP to the level comparable to wildtype patients receiving conventional doses, similar to the principle of TPMT-guided thiopurine dose reduction. To test this hypothesis, we propose three specific aims to 1) comprehensively identify MP toxicity-related NUDT15 and TPMT ALL (N=1,028), 2) characterize the effects of NUDT15 and characterize how NUDT15 and variants influence thiopurine disposition in children with ALL (N=1,550), TPMT variants variants in children with on its function, and finally 3) TPMT from which to develop a NUDT15-/TPMT-based pharmacogenetic algorithm for MP dose adjustments. Successful completion of these studies is likely to establish a novel precision medicine paradigm for thiopurine therapy to proactively individualize dose before toxicity occurs. We are confident that this highly translational project will likely have immediate impact on the treatment of ALL, and our findings can be readily extrapolated to thiopurine therapy for non-malignant conditions (e.g., IBD) thus impact a large number of patients.