PROJECT 3: A High Content Clinical Trial of the MEK inhibitor Trametinib in JMML

项目 3：MEK 抑制剂 Trametinib 在 JMML 中的高内涵临床试验

基本信息

批准号：
10270583
负责人：
KEVIN M. SHANNON
金额：
$ 38.75万
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 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10270583
关键词：
Acute Myelocytic Leukemia Address Alleles Azacitidine Behavior Biological Biological Assay Biological Models Bromodomain CBL gene Cells Child Clinical Clinical Trials DNA Methylation Data Development Diagnosis Diagnostic Diagnostic tests Dysmyelopoietic Syndromes Enrollment Epigenetic Process Europe European Funding Gene Frequency Gene Targeting Genes Genetically Engineered Mouse Genotype Goals Hematopoietic Hematopoietic Stem Cell Transplantation Infant Insertional Mutagenesis Intervention Japan Juvenile Myelomonocytic Leukemia KRAS2 gene KRASG12D Laboratory Study MEKs Malignant Neoplasms Modeling Molecular Molecular Genetics Monitor Mus Mutant Strains Mice Mutation Myeloproliferative disease NF1 gene Neurofibromatosis 1 Newly Diagnosed Oncogenic Outcome PTPN11 gene Pathogenesis Pathologic Pathology Pathway interactions Patients Phase II Clinical Trials Prognosis Ras/Raf Refractory Relapse Reproducibility Research Project Grants Resistance Role Sampling Signal Transduction Somatic Mutation Specimen Transgenes Translational Research Tumor Suppressor Genes Work base candidate marker chemotherapy clinical translation conditional mutant founder mutation high risk hyperactive Ras improved inhibitor/antagonist innovation kinase inhibitor methylation pattern molecular targeted therapies mutant next generation novel novel marker pre-clinical preclinical study preclinical trial predictive marker response response biomarker risk stratification standard of care tumor working group

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) for which the standard of care is hematopoietic stem cell transplant (HSCT). Unfortunately, relapse rates are high after HSCT, particularly in NF1 patients. We discovered that NF1 functions as a tumor suppressor gene in hematopoietic cells and showed that NF1 inactivation results in deregulated Ras/Raf/MEK/ERK signaling. This work suggested a central role of hyperactive Ras signaling in JMML pathogenesis, and our group and others subsequently identified mutations in other Ras pathway genes including NRAS, KRAS, PTPN11, and CBL. Ras pathway mutations are invariably present at high allelic frequency at both diagnosis and relapse. Progression to acute myeloid leukemia (AML) occurs in 20-30% of JMML patients and is frequently associated with outgrowth of subclones that harbor secondary mutations, most commonly in SETBP1 or SH2B3. Consistent with the molecular genetics of JMML, using the Mx1-Cre transgene to inactivate the conditional mutant Nf1flox allele generated or to express oncogenic KrasG12D or NrasG12D in hematopoietic cells induces a JMML-like MPN in mice. We utilized these genetically engineered mouse (GEM) models to perform preclinical trials and observed remarkable efficacy of MEK inhibitors in Kras and Nf1 mutant mice with MPN. During this initial cycle of SPORE funding, we opened a national phase 2 clinical trial of the MEK inhibitor trametinib for patients with relapsed/refractory JMML (ADVL1521) and have observed objective responses in patients treated to date. Enrollment is ongoing and we are collaborating with Cores B (Omics) and C (Pathology) to perform correlative molecular and pathologic analyses. We also developed sensitive and reproducible assays for monitoring molecular responses during the current funding period that we deployed to address additional translational research questions. Finally, we collaborated with colleagues in Europe and Japan to identify global DNA methylation as a novel biomarker of outcome with the most hypermethylated samples portending the worst prognosis independent of genotype. We will extend these novel observations through the following aims: Aim 1. To conduct innovative clinical trials for patients with JMML that emanate from our laboratory and preclinical studies. We will complete the ongoing ADVL1521 trial and have developed the first interventional risk-stratified clinical trial in newly diagnosed JMML; and, Aim 2. To perform biologic and preclinical studies of promising therapies in JMML patient specimens and GEM models to inform clinical translation. Our overall goal is to develop more effective and less toxic therapies for infants and children with JMML by targeting the underlying molecular pathogenesis. These studies also have implications for the fundamental problem of improving the treatment of other cancers driven by hyperactive Ras signaling.

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)，一种侵袭性骨髓增生性肿瘤 (MPN)，其护理标准是造血干细胞移植（HSCT）。不幸的是，HSCT 后复发率很高，尤其是 NF1 患者。我们发现 NF1 在造血细胞中充当肿瘤抑制基因，并表明 NF1 失活导致 Ras/Raf/MEK/ERK 信号传导失调。这项工作表明了核心作用 JMML 发病机制中过度活跃的 Ras 信号传导，我们的小组和其他人随后发现其他 Ras 通路基因的突变，包括 NRAS、KRAS、PTPN11 和 CBL。 Ras途径突变在诊断和复发时总是以高等位基因频率存在。进展为急性髓系细胞白血病 (AML) 发生在 20-30% 的 JMML 患者中，并且通常与白血病的生长有关带有二次突变的亚克隆，最常见的是 SETBP1 或 SH2B3。符合 JMML 的分子遗传学，使用 Mx1-Cre 转基因灭活条件突变 Nf1flox 等位基因在造血细胞中产生或表达致癌性 KrasG12D 或 NrasG12D 会在造血细胞中诱导 JMML 样 MPN 老鼠。我们利用这些基因工程小鼠 (GEM) 模型进行临床前试验并观察到 MEK 抑制剂对患有 MPN 的 Kras 和 Nf1 突变小鼠具有显着疗效。在这个最初的在 SPORE 资助周期内，我们启动了 MEK 抑制剂曲美替尼 (Trametinib) 的国家 2 期临床试验患有复发/难治性 JMML (ADVL1521) 的患者，并观察到患者的客观反应治疗至今。招募正在进行中，我们正在与核心 B（组学）和 C（病理学）合作进行相关的分子和病理分析。我们还开发了灵敏且可重复的在我们部署的当前资助期内监测分子反应的分析其他转化研究问题。最后，我们与欧洲和日本的同事合作，将全球 DNA 甲基化确定为甲基化程度最高的样本结果的新型生物标志物预示着最差的预后，与基因型无关。我们将通过以下方式扩展这些新颖的观察结果目标如下：目标 1. 对源自我们的 JMML 患者进行创新的临床试验实验室和临床前研究。我们将完成正在进行的 ADVL1521 试验并开发出首个针对新诊断 JMML 的介入风险分层临床试验；目标 2. 进行生物和在 JMML 患者标本和 GEM 模型中对有希望的疗法进行临床前研究，为临床提供信息翻译。我们的总体目标是为婴儿和儿童开发更有效、毒性更小的疗法通过针对潜在的分子发病机制来使用 JMML。这些研究也对改善由过度活跃的 Ras 信号驱动的其他癌症的治疗的根本问题。