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(NF1)的标志性表现，可影响多达 50%的患者，并导致终生发病率。PNF进展为不典型神经纤维瘤(ANF)和/或 恶性周围神经鞘瘤(MPNST)。这些难治性肉瘤代表了 NF1患者的主要死亡原因。临床基因组研究与新型基因工程小鼠 由项目1调查人员领导和开发的(GEM)模型提供了强有力的证据，表明 CDKN2a(Ink4a)和/或其交替阅读框(ARF)是大多数NF1- 关联的ANF和MPNST。这些模型将作为描述以下关键事件的易处理平台 PNF向MPNST的演变，以及对新的实验疗法的临床前评估。 到目前为止，我们的研究已经确定了PNF的前两种广泛临床有效的药物，MEK抑制剂， Selumetinib和多RTK抑制剂Cabozantinib。来自临床前模型和初始阶段的机械论见解 2期试验表明，赛鲁米替尼和库赞替尼具有不同的药效学特征。 肿瘤雪旺细胞内的分子靶点以及肿瘤微环境。 总而言之，这些结果表明，将这两种药物联合使用可能会提高PNF的疗效，或许 阻碍进展为ANF和MPNST。杂合子NF1突变型肿瘤微环境 在PNF开发中至关重要，因此是实现更有效组合的关键考虑因素 治疗。尽管胶原和其他细胞外基质(ECM)蛋白是PNF的主要成分 在微环境中，它们各自在肿瘤启动和维持中的作用尚不清楚。 为正在进行的为受肿瘤影响的NF1患者开发新疗法的翻译工作提供信息 在PNF-ANF-MPNST连续体中，我们将完成以下工作：(1)确定可操作的治疗靶点 在肿瘤微环境中与肿瘤相互作用的NF1+/-成纤维细胞和ECM蛋白中 雪旺细胞加速PNF的形成和维持；(2)延长新型GEM和 PDX模型研究联合治疗(包括Meki、Beti、SHP-2和 Cabozantinib)治疗现有的PNF、ANF和MPNST以及预防 先兆病变；(3)进行Meki和卡波占丁联合治疗的早期临床试验 PNF可能延伸到更晚期的神经鞘瘤(ANF和MPNST)，根据正在进行的信息 临床前研究；(4)利用OMICS(核心B)和生物显微镜/病理学方面的最新技术 (CORE C)确定PNF、ANF和MPNST在GEM模型和患者活检中的适应性反应 通过评估基因组、转录组和功能丰富的基因组组前后的样本 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.