Project 1: Molecular and Genetic Features Across Mouse and Human Plexiform Neurofibromas to Inform Clinical Trials

项目 1：小鼠和人类丛状神经纤维瘤的分子和遗传特征为临床试验提供信息

• 批准号: 8932162
• 负责人: David W Clapp
• 金额: $ 12.38万
• 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/8932162
• 关键词: Adult; Affect; Aftercare; Age; Biological Markers; Biopsy; Blood Vessels; Body Regions; Bone Marrow; Bone Marrow Transplantation; Cell Aging; Cells; Cessation of life; Child; Childhood; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Complex; Data; Deformity; Development; Developmental Therapeutics Program; Dose; Drug Kinetics; Early identification; Embryo; Excision; Failure; Fibroblasts; Functional disorder; Genetic; Genetically Engineered Mouse; Head and Neck Neoplasms; Hematopoietic; Human; Imatinib; Imatinib mesylate; Immune; Knowledge; Lesion; Location; MAP2K1 gene; MEK inhibition; Mediating; Molecular; Molecular Genetics; Morbidity - disease rate; Mus; NF1 gene; Nerve Tissue; Nervous system structure; Neurofibrosarcoma; Operative Surgical Procedures; Paralysed; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase I Clinical Trials; Plexiform Neurofibroma; Population; Premalignant; Proteins; Proteomics; Proto-Oncogene Protein c-kit; Ras/Raf; Resistance; Schedule; Schwann Cells; Series; Soft Tissue Neoplasms; Staging; Stem Cell Factor; Stem cells; System; Systems Biology; Tamoxifen; Therapeutic; Time; Transcriptional Regulation; Transgenic Organisms; Tumor Burden; Tumor Tissue; chemotherapy; clinical effect; exome; exome sequencing; improved; inhibitor/antagonist; oncology; phase 2 study; phase II trial; preclinical study; response; stem; targeted treatment; transcriptome sequencing; transcriptomics; treatment response; tumor; tumor progression

ABSTRACT – PROJECT 1 Plexiform neurofibromas (pNF) are complex nerve and soft tissue tumors that affect 25-50% of people with NF1. These tumors cause lifelong, progressive morbidity ranging from deformity to paralysis and death. Plexiform neurofibromas are clinically challenging because they involve multiple body regions and encompass critical portions of the nervous system making surgical excision unfeasible. Moreover, they are multicellular, comprised of Schwann cells, blood vessels, fibroblasts and immune cells requiring informed strategies to identify effective drug therapies. In a series of genetic and bone marrow transplantation studies in genetically engineered mice (GEM), the Clapp and Parada groups demonstrated that the Nf1 GEM is relevant to human pNF pathophysiology, that there is a complex interplay between Nf1-/- Schwann cells and the microenvironment, and that targeting this interaction reduces tumor burden in mice. The phase 2 study of imatinib showed impressive tumor response in a subset of patients, however, the majority of tumors did not respond (Robertson et al, Lancet Oncology, 2012). Recent genetic and pharmacologic studies identify the Ras-Raf-Erk pathway as key in NF1 mediated tumors and suggest that Mek inhibition is another important therapeutic strategy for pNF. However, similar to imatinib, there is variable tumor response in both GEM and patients. This raises the question: what factors mediate variable responses in pNF? In order to determine the factors that mediates the variable responses, our group will accomplish the following: (1) explore adaptive responses to Mek inhibition via RNAseq and kinome studies in pre- and post-treatment tumor tissue in patients with pNF treated with the Mek inhibitor selumetinib and investigate circulating hematopoietic stem/progenitor cells before, during and after treatment in patients; (2) evaluate the relationship between treatment response and tumor factors (location, age, and cellular, protein and genetic features before and after treatment) across GEM and patients with NF1; (3) investigate the clinical, molecular and pharmacokinetic (PK) effects of combined c-kit and Mek inhibition in GEM; (4) explore adaptive responses to Mek and c-kit inhibition alone and in combination in GEM via quantitative proteomics, transcriptomics (RNAseq) and exome sequencing in collaboration with Dr. Johnson in the Omics core and (5) investigate the therapeutic window(s) for c-kit inhibition at distinct embryonic and adult stages of pNF formation in GEM.

摘要-项目1 丛状神经纤维瘤（pNF）是复杂的神经和软组织肿瘤，影响25-50%的人， NF 1。这些肿瘤导致终身的、进行性的发病率，从畸形到瘫痪和死亡。 丛状神经纤维瘤在临床上具有挑战性，因为它们涉及多个身体区域， 神经系统的关键部分使得手术切除不可行。此外，它们是多细胞的， 包括雪旺细胞、血管、成纤维细胞和免疫细胞，需要采取明智的策略， 确定有效的药物疗法。在一系列遗传和骨髓移植研究中， Clapp和Parada研究组证明，Nf 1 GEM与人类基因组相关， pNF病理生理学，Nf 1-/-雪旺细胞和pNF之间存在复杂的相互作用。 这种相互作用可以降低小鼠的肿瘤负荷。第二阶段研究 伊马替尼在一部分患者中显示出令人印象深刻的肿瘤反应，然而，大多数肿瘤没有 缓解（Robertson et al，Lancet Oncology，2012）。最近的遗传学和药理学研究表明， Ras-Raf-Erk通路在NF 1介导的肿瘤中起关键作用，并表明Mek抑制是另一个重要的 pNF的治疗策略然而，与伊马替尼类似，GEM和伊马替尼的肿瘤反应不同。 患者这就提出了一个问题：什么因素介导pNF中的可变反应？ 为了确定介导变量响应的因素，我们的小组将完成以下工作： (1)在治疗前和治疗后通过RNAseq和激酶组研究探索对Mek抑制的适应性反应 用Mek抑制剂selumetinib治疗pNF患者的肿瘤组织，并研究循环 造血干/祖细胞在患者治疗前、治疗中和治疗后;（2）评估 治疗反应和肿瘤因素（位置，年龄，细胞，蛋白质和遗传特征， 和治疗后）在GEM和NF 1患者中;（3）研究临床，分子和 在GEM中组合的c-kit和Mek抑制的药代动力学（PK）效应;（4）探索对C-kit和Mek抑制的适应性反应。 通过定量蛋白质组学、转录组学在GEM中单独和联合抑制Mek和c-kit （RNaseq）和外显子组测序，与组学核心中的约翰逊博士合作，并（5）研究 在GEM中pNF形成的不同胚胎和成体阶段c-kit抑制的治疗窗。