Project 3: Efficacy of MEK Inhibition in Juvenile Myelomonocytic Leukemia

项目3：MEK抑制对幼年粒单核细胞白血病的疗效

基本信息

批准号：
8932164
负责人：
KEVIN M. SHANNON
金额：
$ 43.13万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8932164
关键词：
Acute Myelocytic Leukemia Acute leukemia Adult Age Alleles BRAF gene Biological Assay Biological Markers CBL gene Cells Child Childhood Leukemia Chromosomes, Human, Pair 7 Clinical Clinical Trials Cytogenetics Data Development Developmental Therapeutics Program Diagnosis Disease Disease Resistance Dose Drug resistance Enrollment Evolution Gene Frequency Gene Mutation Generations Genes Genetic Genotype Goals Hematopoietic Hematopoietic Stem Cell Transplantation Homologous Gene Human In Vitro Industry Juvenile Myelomonocytic Leukemia KRAS2 gene MEK inhibition MEKs Malignant Neoplasms Modeling Molecular Molecular Genetics Molecular Profiling Monitor Monosomy 7 Mus Mutagens Mutant Strains Mice Mutation Myeloid Leukemia Myeloproliferative disease NF1 gene Neurofibromatosis 1 Newly Diagnosed Oncogenic Outcome PTPN11 gene Pathogenesis Pathology Pathway interactions Patients Pediatric Oncology Group Phase Refractory Relapse Research Personnel Research Project Grants Residual Tumors Resistance Risk Role Second Primary Cancers Signal Transduction Solid Neoplasm Specimen Technology Testing Transgenes Translational Research Tumor Suppressor Genes Tyrosine Kinase Inhibitor United States Food and Drug Administration base cancer cell chemotherapy efficacy testing in vivo inhibitor/antagonist leukemia melanoma mouse model mutant next generation sequencing novel pre-clinical preclinical study resistance mechanism resistance mutation response tumor

项目摘要

ABSTRACT – PROJECT 3 Children with neurofibromatosis type 1 (NF1) are predisposed to juvenile myelomonocytic leukemia (JMML), an aggressive myeloproliferative neoplasm (MPN). The median survival of JMML patients is <1 year without hematopoietic stem cell transplantation (HSCT), and the overall cure rate is ~50% after HSCT. Our studies showing that NF1 functions as a tumor suppressor gene in JMML patients implicated hyperactive Ras signaling in the pathogenesis of this aggressive cancer. Consistent with this hypothesis, subsequent studies uncovered mutations in the NRAS, KRAS, PTPN11, and CBL genes in JMML patients. Despite the routine use of HSCT in JMML, up to 30% of patients progress to acute myeloid leukemia (AML). Consistent with the molecular genetics of JMML, using the Mx1-Cre transgene to inactivate a conditional mutant Nf1flox allele in the hematopoietic compartment induces a JMML-like MPN is induced in mice, and our preclinical studies in this genetically accurate mouse model revealed remarkable efficacy of potent and selective MEK inhibitors. Interestingly, we found that treatment did not eradicate mutant cells, but modulated their proliferation and differentiation in vivo. Based on these studies, Project 3 of this DHART SPORE will pursue two specific aims. First, we will conduct an Investigator-initiated trial of the FDA-approved MEK inhibitor trametinib in relapsed and newly diagnosed JMML. We will also interrogate molecular mechanisms of response and resistance through the use of sensitive residual disease assays that harness next-generation sequencing technologies to monitor mutant allele burden in JMML specimens. We hypothesize that MEK inhibition will markedly reduce or eradicate JMML cells in a subset of children with JMML, and will induce clinical improvement without altering mutant allele frequency in others. We further postulate that a complete genetic response will predict a favorable outcome, and we will interrogate leukemia cells from patients who initially respond to trametinib and then relapse to identify candidate resistance mutations. In Aim 2, we will investigate human JMML cells and use mouse models of MPN and AML characterized by Nf1 inactivation to investigate how secondary mutations identified in JMML specimens influence the response to trametinib, and to functionally validate candidate mechanisms of drug resistance. Project 3 will benefit from and inform the other Projects in this SPORE, and are dependent on the Administrative, Omics, and Biospecimens/Pathology Cores for successfully achieving its goals.

摘要 – 项目 3 患有 1 型神经纤维瘤病 (NF1) 的儿童易患幼年型粒单核细胞白血病 (JMML)，侵袭性骨髓增生性肿瘤 (MPN) 如果没有，JMML 患者的中位生存期<1 年。造血干细胞移植（HSCT），我们的研究表明HSCT后的总体治愈率约为50%。显示 NF1 在 JMML 患者中作为肿瘤抑制基因发挥作用，这与 Ras 信号传导过度活跃有关随后的研究发现，这种侵袭性癌症的发病机制与这一假设相一致。尽管在 JMML 患者中常规使用 HSCT，但 NRAS、KRAS、PTPN11 和 CBL 基因发生突变。 JMML，高达30%的患者进展为急性髓系白血病（AML），与分子生物学一致。 JMML 的遗传学，使用 Mx1-Cre 转基因使条件突变 Nf1flox 等位基因失活造血室诱导小鼠体内诱导出类似 JMML 的 MPN，我们在这方面的临床前研究遗传精确的小鼠模型揭示了有效且选择性的 MEK 抑制剂的显着功效。阴性，我们发现治疗并没有根除突变细胞，而是调节它们的增殖和基于这些研究，DHART SPORE 项目 3 将追求两个具体目标。首先，我们将对 FDA 批准的 MEK 抑制剂曲美替尼 (Trametinib) 进行一项由研究者发起的试验，用于治疗复发性以及新诊断的 JMML，我们还将探讨反应和耐药的分子机制。通过使用敏感的残留病检测，利用下一代测序技术监测 JMML 样本中的突变等位基因负担，我们发现 MEK 抑制将显着减少或根除部分患有 JMML 的儿童中的 JMML 细胞，并将在不改变我们进一步假设，完整的遗传反应将预测其他人的突变等位基因频率。良好的结果，我们将询问最初对曲美替尼有反应的患者的白血病细胞，然后复发以识别候选耐药突变在目标 2 中，我们将研究人类 JMML 细胞和使用以 Nf1 失活为特征的 MPN 和 AML 小鼠模型来研究二次突变如何 JMML 样本中确定的影响曲美替尼反应的因素，并在功能上验证候选药物项目 3 将受益于本 SPORE 中的其他项目，并为其提供信息。依赖于管理、组学和生物样本/病理学核心来成功实现其目标目标。