Genetics-guided Individualization of Thiopurine Therapy

遗传学指导的硫嘌呤治疗个体化

• 批准号: 9411125
• 负责人: Jun J Yang
• 金额: $ 55.85万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-09 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9411125
• 关键词: 6-Mercaptopurine; Acute Lymphocytic Leukemia; Adopted; African; Algorithms; Alleles; Antineoplastic Agents; Apoptosis; Asians; Autoimmune Diseases; Child; Clinical; Clinical Research; Code; DNA; Data; Dose; Dose-Limiting; Enrollment; Enzymes; European; Exposure to; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genets; Genotype; Hematologic Neoplasms; Hematopoietic; Immunosuppressive Agents; Inflammatory Bowel Diseases; Inherited; Laboratory Research; Lead; Malignant Neoplasms; Metabolism; Modeling; Morbidity - disease rate; Non-Malignant; Nucleotides; Patients; Pediatric Oncology Group; Pharmaceutical Preparations; Pharmacogenetics; Pharmacology; Phenotype; Positioning Attribute; RNA Splicing; Reporting; Research Personnel; Risk; Saint Jude Children' s Research Hospital; Sampling; TPMT gene; Testing; Therapeutic Index; Thioguanine; Thiopurine Methyltransferase Deficiency; Toxic effect; Transcriptional Regulation; Treatment Protocols; Untranslated RNA; Variant; base; clinical implementation; cohort; cytotoxic; cytotoxicity; design; in vivo; individualized medicine; leukemia/lymphoma; mortality; novel; patient population; precision medicine; prospective; prototype; risk variant; targeted sequencing; thiopurine; tripolyphosphate

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.

抽象的 硫嘌呤（例如，巯嘌呤 [MP]）对于治疗血液系统恶性肿瘤（白血病和白血病）非常有效。 淋巴瘤）和自身免疫性疾病（炎症性肠病 [IBD]）。急性淋巴细胞白血病 (ALL) 特别是，每天长时间接触 MP 对于治愈这种癌症是必不可少的。然而， 硫嘌呤类药物的治疗指数较窄，具有剂量限制性造血毒性，可导致广泛的 发病率、治疗中断和可能的死亡。因此，临床上有巨大的益处 预先识别有硫嘌呤毒性风险的患者并进行个体化治疗以减轻毒性。硫嘌呤 毒性也很大程度上受到遗传变异的影响，特别是 TPMT 基因的多态性 正如我们小组和其他人所发现的那样。最近，我们报道了 NUDT15 基因中的一个新变体，该变体可导致 核苷酸二磷酸酶活性丧失，活性硫嘌呤代谢物水平过高，急剧增加 MP 诱导的细胞凋亡和患者严重毒性（J Clin Oncol 2015 和未发表的初步研究） 结果）。 因为低活性的 NUDT15 等位基因改变了硫嘌呤的代谢，我们假设我们可以 合理减少遗传 NUDT15 变异体患者的硫嘌呤剂量并调整其暴露量 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， 与TPMT引导硫嘌呤剂量减少的原理类似。为了检验这个假设，我们提出了三个 具体目标是 1) 全面识别 MP 毒性相关的 NUDT15 和 TPMT ALL (N=1,028), 2) 描述了 NUDT15 和 描述 NUDT15 及其变体如何影响 ALL 儿童的硫嘌呤处置 (N=1,550)， TPMT 变体 儿童的变异 其功能，最后3） TPMT 从中开发基于 NUDT15-/TPMT 的药物遗传学算法，用于 MP 剂量调整。 这些研究的成功完成可能会为硫嘌呤建立一个新的精准医学范例 在毒性发生之前主动个体化剂量的治疗。我们相信，这种高度转化的 项目可能会对 ALL 的治疗产生直接影响，我们的研究结果可以很容易地推断出来 因此，硫嘌呤治疗非恶性疾病（例如 IBD）影响了大量患者。