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，胃嘌呤[MP]）对血液学恶性肿瘤非常有效（白血病和 淋巴瘤）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 （全部）特别是，每天长时间暴露于MP对于治愈这种癌症是必不可少的。然而， 硫嘌呤具有狭窄的治疗指数，并具有限制剂量的造血毒性，导致广泛 发病率，治疗中断以及可能的死亡率。因此，从 先发制人地识别有硫嘌呤毒性和个性化疗法的患者以减轻硫嘌呤的毒性。硫嘌呤 毒性也受到遗传遗传变异的高度影响，尤其是TPMT基因中的多态性 正如我们小组和其他人发现的那样。最近，我们报道了NUDT15基因中的一种新型变体，该变体导致 核苷酸双磷酸酶活性的丧失，活性硫嘌呤代谢物的过多水平，急剧增加 在MP诱导的患者凋亡和严重毒性中（J Clin Oncol 2015和未发表的初步 结果）。 因为低活性NUDT15等位基因会改变硫嘌呤的代谢，所以我们假设我们可以 继承NUDT15变体的患者中，合理地降低硫嘌呤剂量并量身定制其接触 硫嘌呤活性代谢物TGTP达到的水平与接受常规剂量的野生型患者相当， 类似于TPMT引导的硫嘌呤剂量还原原理。为了检验这一假设，我们提出了三个 具体目的是1）全面确定MP毒性相关的NUDT15和 TPMT 所有（n = 1,028），2）表征Nudt15和 表征NUDT15和变体如何影响所有儿童（n = 1,550）， TPMT 变体 儿童的变体 在其功能上，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种新颖的精密医学范式 在毒性发生之前主动剂量的治疗。我们相信这种高度翻译 项目可能会立即对所有人的治疗产生影响，我们的发现很容易被推断 因此，硫嘌呤治疗非机敏状况（例如，IBD）会影响大量患者。