Identification of therapeutic windows for NF1-related malignant peripheral nerve

NF1相关恶性周围神经治疗窗口的确定

• 批准号: 8395374
• 负责人: YUAN ZHU
• 金额: $ 21.5万
• 依托单位: SARC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8395374
• 关键词: Autologous; Axon; Benign; Cafe-au-Lait Spot; Cell Communication; Cell Line; Cells; Cessation of life; Chemoprevention; Clinical; Collection; Complex; Defect; Development; Diffuse; Disease; Drug resistance; Ensure; Excision; Exhibits; General Hospitals; Genetic; Genetically Engineered Mouse; Genomics; Goals; Growth; Human; Individual; Investigation; Laboratories; Lesion; MAP Kinase Gene; MAPK Signaling Pathway Pathway; Malignant - descriptor; Malignant Peripheral Nerve Sheath Tumor; Massachusetts; Mediating; Michigan; Mitogen-Activated Protein Kinases; Mitogens; Modeling; Molecular; Mutation; Nerve; Neural Crest; Neurofibromatosis 1; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patients; Peripheral Nerve Sheath; Peripheral Nerve Sheath Neoplasm; Peripheral Nerves; Phase; Plexiform Neurofibroma; Population; Prevention; Prevention strategy; Process; Protocols documentation; Radiation therapy; Recurrence; Regulation; Schwann Cells; Series; Signal Pathway; Signal Transduction; Staging; Stem cells; Testing; Therapeutic; Tissues; Tumor Cell Line; Universities; Xenograft Model; Xenograft procedure; base; chemotherapy; expectation; extracellular; follow-up; high risk; human tissue; inhibitor/antagonist; insight; melanocyte; mouse model; neoplastic; novel; preclinical study; prevent; research study; resistance mechanism; response; sarcoma; soft tissue; treatment strategy; tumor

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.

恶性外周神经鞘瘤（MPNST）是一种遗传复杂的软组织肉瘤， 肉瘤特异性死亡的最高风险之一，这可能归因于其有限的反应， 传统的化疗和放疗以及其侵入性生长通常阻止完全的外科手术， 切除术这些临床观察强调了对基于更大的 了解MPNST的分子和细胞发病机制。超过50%的MPNST被识别 在患有1型神经纤维瘤病（NFI）的个体中。NF 1相关的MPNST通常发生在 良性周围神经鞘瘤（PNST），丛状神经纤维瘤（PNF）， 假设为多能神经嵴干细胞中NF 1失活引起的先天性病变 （NCSC）神经发育过程中。因此，NF 1相关的MPNST可能是唯一一种与肿瘤相关的肉瘤。 明确的发育基础和关键的良性前驱病变。因此，预防治疗可以 合理的期望。最近的研究表明，NF 1的缺失激活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。 然而，我们使用基因工程小鼠（6 EM）模型的初步研究表明，尽管 Erk/MAPK在癌前病变和良性病变中的一致激活，近一半的MPNST没有表现出 Erk/MAPK激活。这项建议的整体目标是确定多能非公务员合约雇员是否 对于一个丛状神经纤维瘤亚群，具有高复发和恶性潜能， 转换（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 形成（目标2）。最后，我们试图定义一个子集的MPNST，将响应MEKi（目标3）。所有 三个目标提供了通向预防战略和/或治疗战略的途径， 现代遗传实验室研究适当的人体组织，以及进一步发展， 这种疾病过程的小鼠模型。