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

摘要-项目1 丛状神经纤维瘤是一种复杂的神经和软组织肿瘤，影响25%-50%的人 NF1。这些肿瘤会导致终生、渐进性的疾病，包括畸形、瘫痪和死亡。 丛状神经纤维瘤是临床上具有挑战性的肿瘤，因为它们累及多个身体部位。 神经系统的关键部位使手术切除变得不可行。此外，它们是多细胞的， 由雪旺细胞、血管、成纤维细胞和免疫细胞组成，需要知情的策略 确定有效的药物疗法。在一系列遗传学和骨髓移植研究中 工程小鼠(GEM)、Clapp和Parada小组证明了NF1 GEM与人类相关 Nf1-/-雪旺细胞与PNF细胞之间存在复杂的相互作用。 微环境，靶向这种相互作用可以减少小鼠的肿瘤负担。第二阶段的研究 伊马替尼在一小部分患者中显示出令人印象深刻的肿瘤反应，然而，大多数肿瘤患者没有表现出明显的肿瘤反应。 回应(Robertson等人，《柳叶刀肿瘤学》，2012年)。最近的遗传学和药理学研究发现 Ras-Raf-Erk通路在NF1介导的肿瘤中的关键作用，提示MEK抑制是另一个重要的因素 PNF的治疗策略。然而，与伊马替尼类似，GEM和GEM中都有不同的肿瘤反应 病人。这就提出了一个问题：是什么因素调节了pNF中的可变反应？ 为了确定影响变量反应的因素，我们小组将完成以下工作： (1)通过RNAseq和动态组研究探讨治疗前后对MEK抑制的适应性反应 MEK抑制剂塞鲁米替尼治疗pNF患者的肿瘤组织及循环研究 患者治疗前、治疗中和治疗后的造血干/祖细胞；(2)评价两者之间的关系 治疗反应与肿瘤因素(位置、年龄、细胞、蛋白质和遗传特征)之间的关系 和治疗后)；(3)研究临床、分子和 C-kit和MEK联合抑制在GEM中的药代动力学(PK)效应；(4)探讨对 MEK和c-kit在GEM中单独和联合抑制的定量蛋白质组学、转录组学研究 (RNAseq)和外显子组测序，与OMICS的Johnson博士合作，(5)研究 治疗窗口(S)的c-kit抑制在不同的胚胎和成体阶段的pnf形成的宝石。

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.