Investigating and Targeting Pathways of Malignant Peripheral Nerve Sheath Tumor (MPNST)

项目摘要 恶性周围神经鞘瘤（MPNST）是肉瘤特异性死亡率最高的肿瘤之一。 近一半的MPNST来自1型神经纤维瘤病（NF1）患者，是MPNST的主要病因 这些患者的死亡率。NF1患者携带NF1中的生殖系杂合失活突变 肿瘤抑制基因NF1编码RAS-GT3激活蛋白（RAS-GAP），一种负调节因子， RAS介导的信号通路包括RAF/MEK/ERK和PI3K/AKT/mTORC信号通路。 剩余NF 1野生型等位基因的失活驱动了关键良性前驱病变的形成 MPNST，丛状神经纤维瘤（PNF），在30%-50%的NF1患者中观察到。遗传学研究 表明PNF-到-MPNST的进展需要另外的途径的失活，包括（1） 通过编码肿瘤的TP53或CDKN2A的突变/缺失使p53通路失活 抑制基因INK4A和ARF，和（2）多梳阻遏复合物2（PRC2）的损失，通过靶向 SUZ12或EED。尽管没有PNF，但大多数非NF1相关的散发性和辐射诱导的 MPNST也携带这三个途径的遗传改变，因此被认为是MPNST核心 途径。尽管最近在了解MPNST发病机制方面取得了进展， 目前有效的治疗方法除了完全手术切除MPNST外， 由于其位置深和侵入性生长模式，因此是可行的。因此，新疗法的开发 MPNST是迫切需要的。本提案的主要目标是调查和针对这三个 MPNST核心通路作为一种策略，为这种无法治愈的人类癌症开发新的疗法。在目标1中， 我们将检验这样的假设，即通过MEK增强p53介导的凋亡反应的治疗策略， 抑制将为具有野生型TP 53的CDKN 2A缺陷型MPNST提供有效的治疗。我们将建立 针对这两种MPNST的两种临床现成药物的机制基础和治疗效果 一系列MPNST临床前模型的核心通路，包括低传代细胞系、同种异体移植物和 GEM模型，以及人MPNST衍生的细胞系和异种移植模型。在目标2中，我们将确定 PRC2缺失在肿瘤发生、进展和治疗脆弱性中的分子机制 MPNST。我们将研究一系列新的MPNST模型失活所有三个MPNST核心途径， 建立通过PRC2缺失诱导的重编程获得干细胞特征的分子基础，或 在PNF到MPNST转变期间的去分化。我们的工作重点是开发治疗策略 特别是PRC2-熟练和PRC2-缺陷MPNST。

Project Abstract Malignant peripheral nerve sheath tumors (MPNST) cause one of the highest rates of sarcoma-specific death. Nearly half of MPNSTs arise from individuals with neurofibromatosis type 1 (NF1), representing a leading cause of death in these patients. NF1 patients carry germline heterozygous inactivating mutations in the NF1 tumor suppressor gene. NF1 encodes a RAS-GTPase Activating Protein (RAS-GAP), a negative regulator of RAS-mediated signaling pathways including RAF/MEK/ERK and PI3K/AKT/mTORC signaling pathways. Inactivation of the remaining NF1 wild-type alleles drives the formation of a critical benign precursor lesion of MPNST, plexiform neurofibroma (PNF) that is observed in 30%-50% of NF1 patients. Genetic studies have shown that the progression of PNF-to-MPNST requires inactivation of additional pathways including (1) inactivation of the p53 pathway, either by mutations/deletions of TP53 or CDKN2A that encodes tumor suppressor genes INK4A and ARF, and (2) loss of the Polycomb repressor complex 2 (PRC2), by targeting SUZ12 or EED. Despite the absence of PNFs, most non-NF1-associated sporadic and radiation-induced MPNSTs also carry genetic alterations in these three pathways, and hence are considered as MPNST core pathways. Despite recent progress in understanding the mechanism underlying MPNST pathogenesis, no effective therapy is currently available except for complete surgical resection of MPNST, which is often not feasible due to its deep location and invasive growth pattern. Thus, the development of new therapies for MPNSTs is urgently needed. The main objective of this proposal is to investigate and target these three MPNST core pathways as a strategy to develop novel therapies for this incurable human cancer. In Aim 1, we will test the hypothesis that therapeutic strategies enhancing p53-mediated apoptotic responses by MEK inhibition will present an effective therapy for CDKN2A-deficient MPNSTs with wild-type TP53. We will establish the mechanistic basis and therapeutic efficacy of two clinically ready drugs that target these two MPNST core pathways in a series of preclinical models of MPNSTs including low-passage cell lines, allograft and GEM models, as well as human MPNST-derived cell lines and xenograft models. In Aim 2, we will identify molecular mechanisms underlying PRC2 loss in the initiation, progression and therapeutic vulnerability of MPNSTs. We will investigate a series of novel MPNST models inactivating all three MPNST core pathways and establish the molecular basis of acquiring stem-cell characteristics by PRC2 loss-induced reprogramming or de-differentiation during the PNF-to-MPNST transition. Our work focuses on developing therapeutic strategies specifically for PRC2-proficient and PRC2-deficient MPNSTs.