The role of mTORC1 in the development and therapeutic targeting of NF1-associated

描述（由申请人提供）：1型神经纤维瘤病（NF1）的标志性特征是周围神经系统（PNS）中多发性良性周围神经鞘肿瘤（PNST）的发展，也称为神经纤维瘤。其中一种神经纤维瘤亚型，即丛状神经纤维瘤，可发生在功能关键的神经上，并弥漫性浸润神经，引起神经系统疾病，这些疾病很少能通过手术治愈。此外，丛状神经纤维瘤是唯一一种可能发生恶性转化并进展为恶性周围神经鞘肿瘤（MPNSTs）的神经纤维瘤亚型。MPNST是NF1患者死亡的主要原因，特别是对于40岁以下的患者。这些PNS癌症对传统的化疗和放疗具有耐药性。此外，典型的深部位置和局部侵袭性生长往往阻碍mpnst的完全手术切除。因此，所有年龄段NF1和mpnst患者的5年生存率都很差，约为21%。总之，这些临床观察强调了迫切需要基于对NF1相关丛状神经纤维瘤和mpnst的分子和细胞机制的更深入理解的新疗法。我们最近开发了一系列神经纤维瘤和MPNST基因工程小鼠（GEM）模型，这些模型概括了人类PNST的进行性本质。这些新开发的GEM神经纤维瘤和MPNST模型，首次使我们能够评估关键分子途径的作用和抗肿瘤药物在PNST发展的所有阶段的治疗效果。特别是，我们已经确定了关键的细胞和分子事件在PNST发展的早期阶段。根据我们的初步数据，我们假设哺乳动物雷帕霉素靶蛋白复合物1 （mTORC1）活性并不总是升高，而是在PNST的发生、进展和恶性转化过程中动态调节。本提案的目的是系统地研究mTORC1信号传导和雷帕霉素在PNST的发生、进展和恶性转化中的治疗作用。这些研究旨在确定潜在的治疗窗口，可以在早期阶段针对丛状神经纤维瘤和MPNST。具体而言，我们将(1)确定外周神经鞘肿瘤发展早期mTORC1信号抑制的表型后果；(2)确定动态调节的mTORC1活性在外周神经鞘肿瘤发展中的作用。这一建议不仅将对mtorc1介导的信号通路在PNST发展的各个阶段的作用提供重要的见解，而且将系统地评估雷帕霉素在PNST的发生、进展和恶性转化中的治疗作用。

DESCRIPTION (provided by applicant): The hallmark feature of Neurofibromatosis type 1 (NF1) is the development of multiple benign peripheral nerve sheath tumors (PNST), also known as neurofibromas, in the peripheral nervous system (PNS). One neurofibroma subtype, plexiform neurofibroma, can arise in functionally critical nerves and diffusely infiltrate through the nerves, causing neurological problems that only rarely can be cured by surgery. Moreover, plexiform neurofibroma is the only neurofibroma subtype with the potential to undergo malignant transformation and progress to malignant peripheral nerve sheath tumors (MPNSTs). MPNST is a major cause of death in individuals with NF1, particularly for those younger than 40 years of age. These PNS cancers are resistant to conventional chemo- and radiotherapies. Furthermore, the typical deep location in the body and locally invasive growth often prevent complete surgical resection of MPNSTs. Consequently, the 5-year survival rate of all ages with NF1 and MPNSTs is poor, approximately 21%. Together, these clinical observations emphasize the urgent need for novel therapies based upon a greater understanding of the molecular and cellular mechanisms that underlie NF1- associated plexiform neurofibromas and MPNSTs. We recently have developed a series of neurofibroma and MPNST genetically engineered mouse (GEM) models that recapitulate the progressive nature of human PNST. These newly developed GEM neurofibroma and MPNST models, for the first time, enable us to assess the role of a critical molecular pathway(s) and therapeutic effects of an anti-tumor agent(s) during all stages of PNST development. Particularly, we have identified critical cellular and molecular events in the earliest stages of PNST development. Based upon our preliminary data, we hypothesize that the mammalian target of rapamycin complex 1 (mTORC1) activity is not always elevated, but instead dynamically regulated during initiation, progression, and malignant transformation of PNST. The objectives of this proposal are to systematically examine the role of mTORC1 signaling and therapeutic effects of rapamycin in the initiation, progression, and malignant transformation of PNST. These studies aim to identify potential therapeutic windows that can target plexiform neurofibroma and MPNST at the earliest stages. Specifically, we will (1) determine phenotypic consequences of inhibition of mTORC1 signaling during early phases of peripheral nerve sheath tumor development and (2) determine the role of dynamically regulated mTORC1 activity in peripheral nerve sheath tumor development. This proposal not only will provide important insights into the role of the mTORC1-mediated signaling pathway in all stages of PNST development, but also will systematically assess therapeutic effects of rapamycin in the initiation, progression and malignant transformation of PNST.