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

• 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
• 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

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）。 JMML 患者的中位生存期<1 年 造血干细胞移植（HSCT），HSCT后总体治愈率约为50%。我们的研究 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 这种侵袭性癌症的发病机制。随后的研究发现，与这一假设相一致 JMML 患者的 NRAS、KRAS、PTPN11 和 CBL 基因突变。尽管 HSCT 已常规使用 JMML，高达 30% 的患者进展为急性髓系白血病 (AML)。与分子一致 JMML 的遗传学，使用 Mx1-Cre 转基因使条件突变体 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 基因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。 有趣的是，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增殖 体内分化。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抵抗的分子机制 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荷。我们假设 MEK 抑制会显着减少或 根除一部分患有 JMML 的儿童中的 JMML 细胞，并将在不改变 其他人的突变等位基因频率。我们进一步假设完整的遗传反应将预测 良好的结果，我们将检查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 耐药机制。项目 3 将受益于该 SPORE 中的其他项目并为其提供信息，并且 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。