PROJECT 1: From Neurofibroma to MPNST: Models, Biology and Translation to Clinic

项目 1：从神经纤维瘤到 MPNST：模型、生物学和临床转化

• 批准号: 10494103
• 负责人: David W Clapp
• 金额: $ 54.09万
• 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 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10494103
• 关键词: Adult; Affect; Aftercare; Award; Benign; Biological; Biology; Biopsy Specimen; Bromodomain; CDKN2A gene; Caring; Cause of Death; Cessation of life; Characteristics; Childhood; Clinic; Clinical; Clinical Research; Clinical Trials; Collagen; Combined Modality Therapy; Complex; Data; Deformity; Development; Evaluation; Event; Evolution; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Funding; Genetic study; Genetically Engineered Mouse; Genome; Genomics; Goals; Histologic; Human; In complete remission; Indolent; Investigational Therapies; Laboratories; Lesion; MEKs; Maintenance; Malignant - descriptor; Modeling; Molecular Analysis; Molecular Target; Morbidity - disease rate; Mutation; Neoplastic Schwann Cell; Nerve; Nerve Sheath Tumors; Neurofibromatosis 1; Neurofibrosarcoma; Operative Surgical Procedures; PTPN11 gene; Paralysed; Pathology; Patients; Pharmaceutical Preparations; Pharmacodynamics; Play; Plexiform Neurofibroma; Pre-Clinical Model; Prevention; Preventive; Property; Radiation; Reading Frames; Refractory; Research Personnel; Role; Sampling; Schwann Cells; Signal Transduction; Structure; Systems Biology; Technology; Testing; Therapeutic; Therapeutic Studies; Translating; Translations; anticancer treatment; chemotherapy; clinical translation; early phase clinical trial; hyperactive Ras; improved; inhibitor; insight; molecular targeted therapies; mortality; mouse model; multimodality; mutant; neurofibroma; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; phase II trial; pre-clinical; preclinical evaluation; preclinical study; premalignant; premature; prevent; programs; response; sarcoma; synergism; therapeutic target; tool; transcriptome; translational clinical trial; translational study; tumor; tumor initiation; tumor microenvironment; tumorigenic

ABSTRACT (Project 1) Plexiform neurofibromas (PNF) are a hallmark manifestation of neurofibromatosis type 1 (NF1) that affect up to 50% of patients and causes lifelong morbidity. A subset of PNF progress to atypical neurofibroma (ANF) and/or malignant peripheral nerve sheath tumors (MPNST). These treatment refractory sarcomas represent the leading cause of death in NF1 patients. Clinical genomic studies and novel genetically engineered mouse (GEM) models, led and developed by Project 1 investigators, have provided strong evidence that loss of CDKN2A (INK4A) and/or its alternate reading frame (ARF) is a key driver event in the majority of NF1- associated ANF and MPNST. These models will serve as tractable platforms for characterizing key events in the evolution of PNF to MPNST, and for preclinical evaluation of novel experimental therapeutics. Our studies to date have identified the first two broadly clinically effective drugs for PNF, the MEK inhibitor, selumetinib, and the multi-RTK inhibitor, cabozantinib. Mechanistic insights from preclinical models and initial phase 2 trials showed that selumetinib and cabozantinib have distinct pharmacodynamic characteristics, in both the molecular targets within neoplastic Schwann cells as well as the tumor microenvironment. Collectively, these results suggest that combining these two drugs may enhance efficacy in PNF, and perhaps impede the progression to ANF and MPNST. The heterozygous NF1 mutant tumor microenvironment is essential in PNF development, and thus is a key consideration for implementing more effective combination therapies. Although collagen and other extracellular matrix (ECM) proteins are primary constituents of the PNF microenvironment, their respective roles in tumor initiation and maintenance remain unexplored. To inform ongoing translational efforts to develop novel therapies for NF1 patients affected by tumors across the PNF-ANF-MPNST continuum, we will accomplish the following: (1) Identify actionable therapeutic targets within NF1+/- fibroblasts and ECM proteins of the tumor microenvironment that interact with neoplastic Schwann cells to accelerate PNF formation and maintenance; (2) Extend preclinical studies in novel GEM and PDX models to investigate potential synergism of therapeutic combinations (including MEKi, BETi, SHP-2, and cabozantinib) in treating existing PNF, ANF and MPNST as well as in preventing malignant transformation of precursor lesions; (3) Conduct an early phase clinical trial of MEKi and cabozantinb combination therapy in PNF that may extend to more advanced nerve sheath tumors (ANF and MPNST) as informed by ongoing preclinical studies; (4) Leverage state-of-the-art technologies in Omics (Core B) and Biospecimen/Pathology (Core C) to define adaptive responses of PNF, ANF, and MPNST in GEM models as well as patient biopsy specimens by evaluation of the genome, transcriptome, and functionally enriched kinome before and after treatment.

摘要（项目1） 丛状神经纤维瘤 (PNF) 是 1 型神经纤维瘤病 (NF1) 的标志性表现，影响最多 50%的患者会导致终生发病。 PNF 的一部分进展为非典型神经纤维瘤 (ANF) 和/或 恶性周围神经鞘瘤（MPNST）。这些难治性肉瘤代表了 NF1 患者死亡的主要原因。临床基因组研究和新型基因工程小鼠 由项目 1 研究人员领导和开发的（GEM）模型提供了强有力的证据，证明 CDKN2A (INK4A) 和/或其替代阅读框架 (ARF) 是大多数 NF1- 中的关键驱动事件 相关的 ANF 和 MPNST。这些模型将作为易于处理的平台来描述关键事件的特征 PNF 到 MPNST 的演变，以及新型实验疗法的临床前评估。 迄今为止，我们的研究已经确定了前两种临床广泛有效的 PNF 药物，即 MEK 抑制剂， 司美替尼（selumetinib）和多 RTK 抑制剂卡博替尼（cabozantinib）。来自临床前模型和初始的机制见解 2期试验表明，selumetinib和cabo​​zantinib具有不同的药效学特征， 肿瘤雪旺细胞内的分子靶标以及肿瘤微环境。 总的来说，这些结果表明结合这两种药物可能会增强 PNF 的疗效，并且也许 阻碍 ANF 和 MPNST 的进展。杂合的 NF1 突变肿瘤微环境是 在PNF开发中至关重要，因此是实施更有效组合的关键考虑因素 疗法。尽管胶原蛋白和其他细胞外基质 (ECM) 蛋白是 PNF 的主要成分 微环境中，它们各自在肿瘤发生和维持中的作用仍有待探索。 为正在进行的转化工作提供信息，为受肿瘤影响的 NF1 患者开发新疗法 PNF-ANF-MPNST 连续体，我们将完成以下任务：（1）确定可行的治疗目标 在与肿瘤相互作用的肿瘤微环境的 NF1+/- 成纤维细胞和 ECM 蛋白中 雪旺细胞加速 PNF 形成和维持； (2) 扩大新型 GEM 和 PDX 模型用于研究治疗组合（包括 MEKi、BETi、SHP-2 和 卡博替尼 (cabozantinib) 治疗现有的 PNF、ANF 和 MPNST 以及预防恶性转化 前兆病变； （3）开展MEKi与卡博赞汀联合治疗的早期临床试验 根据正在进行的研究，PNF 可能会扩展到更晚期的神经鞘瘤（ANF 和 MPNST） 临床前研究； (4) 利用组学（核心 B）和生物样本/病理学领域最先进的技术 （核心 C）定义 GEM 模型以及患者活检中 PNF、ANF 和 MPNST 的适应性反应 通过评估前后的基因组、转录组和功能富集的激酶组来获取样本 治疗。