Identification of therapeutic windows for NF1-related malignant peripheral nerve

恶性周围神经鞘瘤(MPNST)是一种遗传复杂的软组织肉瘤，具有 肉瘤特异性死亡的最高风险之一，可能归因于它对 传统的化疗和放射治疗及其侵袭性生长往往阻碍了完全的外科手术 切除手术。这些临床观察强调了迫切需要基于更大的 了解MPNST的分子和细胞发病机制。超过50%的MPNST被识别出来 在患有1型神经纤维瘤病(NFI)的患者中。与NF1相关的MPNST通常出现在 良性周围神经鞘膜瘤(PNST)、丛状神经纤维瘤(PNF)亚型 假设为多能神经脊干细胞中NF1失活引起的先天性损害 (NCSCs)在神经发育期间。因此，NF1相关的MPNST可能是唯一具有 明确的发育基础和严重的良性前驱病变。因此，预防治疗可以是 一个合理的预期。最近的研究表明，NF1的缺失激活了RAS介导的细胞外信号-- 调节/丝裂原活化蛋白激酶(ERK/MAPK)信号通路在MPNST细胞系中的表达。 然而，我们使用基因工程小鼠(6EM)模型进行的初步研究表明，尽管 ERK/MAPK在癌前病变和良性病变中的持续激活，近一半的MPNSTs没有表现出 ERK/MAPK激活。这项提案的总体目标是确定多能性NCSC是否是 复发率高的丛状神经纤维瘤的原位细胞治疗 转型(目标1)。此外，我们试图确定在MPNST之前，是否存在关键的 ERK/MAPK通路抑制剂(Meki)可预防PnF和MPNST的治疗窗(S) 队形(目标2)。最后，我们尝试定义将响应Meki的MPNST子集(目标3)。全 三个目标提供了一条通向预防战略和/或治疗战略的途径 现代遗传实验室对适当的人体组织的研究以及进一步的发展 这种疾病过程的小鼠模型。

Malignant peripheral nerve sheath tumors (MPNSTs) are genetically complex soft-tissue sarconnas that have one of the highest risks of sarcoma-specific deaths, which could be attributed to its limited responses to conventional chemo- and radiotherapies as well as its invasive growth that often prevent complete surgical resection. These clinical observations emphasize the urgent need for novel therapies based on a greater understanding of molecular and cellular pathogenesis of MPNST. More than 50% of MPNSTs are identified in individuals afflicted with neurofibromatosis type 1 (NFI). NF1-associated MPNST often arises within a subpopulation of benign peripheral nerve sheath tumor (PNST), plexiform neurofibroma (PNF), which is hypothesized as a congenital lesion caused by NF1 inactivation in multipotent neural crest stem cells (NCSCs) during nerve development. Thus, NF1-associated MPNST may represent the only sarcoma with a defined developmental basis and a critical benign precursor lesion. As such prevention treatments could be a reasonable expectation. Recent studies showed that loss of NF1 activates Ras-mediated extracellularsignal- regulated/mitogen-activated protein kinase (ERK/MAPK) signaling pathway in MPNST cell lines. However, our preliminary studies using genetically engineered mouse (6EM) models showed that despite consistent activation of Erk/MAPK in pre-neoplastic and benign lesions, nearly half of MPNSTs exhibited no Erk/MAPK activation. The overall goal of this proposal is to determine whether multipotent NCSCs are the cell-of-ongin for a subset of plexiform neurofibromas that have high potentials for recurrence and malignant transformation (Aim 1). Furthermore, we attempt to determine whether prior to MPNST, there is a critical therapeutic window(s) in which an ERK/MAPK pathway inhibitor (MEKi) can prevent PNF and MPNST formation (Aim 2). Finally, we attempt to define a subset of MPNSTs that will respond to MEKi (Aim 3). All three aims provide a pathway leading to either a prevention strategy and/or therapeutic strategy based on modern genetic laboratory investigation of appropriate human tissues as well as further development of mouse models of this disease process.