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

摘要（项目1） 丛状神经纤维瘤（PNF）是1型神经纤维瘤病（NF 1）的标志性表现， 50%的患者并导致终身发病。PNF的一个子集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 NF 1患者的主要死亡原因。临床基因组学研究和新型基因工程小鼠 (GEM)由项目1调查人员领导和开发的模型提供了强有力的证据，表明 CDKN 2A（INK 4A）和/或其替代阅读帧（ARF）是大多数NF 1-κ B中的关键驱动事件。 相关ANF和MPNST。这些模型将作为一个易于处理的平台， PNF向MPNST的演变，以及新实验疗法的临床前评价。 迄今为止，我们的研究已经确定了前两种广泛临床有效的PNF药物，MEK抑制剂， 司美替尼和多RTK抑制剂卡博替尼。从临床前模型和初始 2期试验显示司美替尼和卡博替尼具有不同的药效学特征， 肿瘤性雪旺细胞内的分子靶点以及肿瘤微环境。 总的来说，这些结果表明，联合这两种药物可能会提高PNF的疗效， 阻止进展为ANF和MPNST。杂合NF 1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 治疗虽然胶原和其他细胞外基质（ECM）蛋白是PNF的主要成分， 然而，在微环境中，它们各自在肿瘤起始和维持中的作用仍然未被探索。 为正在进行的翻译工作提供信息，以开发针对受肿瘤影响的NF 1患者的新疗法， 在PNF-ANF-MPNST连续体中，我们将完成以下任务：（1）确定可操作的治疗靶点 肿瘤微环境的NF 1 +/-成纤维细胞和ECM蛋白与肿瘤细胞相互作用， 雪旺细胞加速PNF的形成和维持;（2）扩大新型GEM的临床前研究， PDX模型以研究治疗组合（包括MEKi、BETi、SHP-2和MEKi）的潜在协同作用。 卡博替尼）在治疗现有的PNF、ANF和MPNST以及预防恶性转化中的用途。 （3）在早期进行MEKi和卡博替尼联合治疗的临床试验， PNF可能扩展到更晚期的神经鞘肿瘤（ANF和MPNST）， 临床前研究;（4）利用组学（核心B）和生物样本/病理学的最新技术 (Core C）在GEM模型以及患者活检中定义PNF、ANF和MPNST的适应性反应 通过评估基因组、转录组和功能富集的激酶组， 治疗

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.