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

mTORC1 在 NF1 相关疾病的发展和治疗靶向中的作用

• 批准号: 8086146
• 负责人: YUAN ZHU
• 金额: $ 33.4万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8086146
• 关键词: Age; Age-Years; Benign; Cause of Death; Clinical; Complex; Cytostatics; Data; Development; Drug resistance; Event; Excision; Exhibits; Genetic; Genetically Engineered Mouse; Growth; Human Characteristics; Individual; Lesion; Location; Malignant - descriptor; Malignant Neoplasms; Malignant Peripheral Nerve Sheath Tumor; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Nerve; Neurofibromatosis 1; Neurologic; Operative Surgical Procedures; Pathway interactions; Patients; Peripheral Nerve Sheath Neoplasm; Peripheral Nervous System; Phase; Plexiform Neurofibroma; Radiation therapy; Resistance; Role; Series; Signal Pathway; Signal Transduction; Sirolimus; Source; Staging; Survival Rate; Therapeutic; Therapeutic Effect; Time; Tumor Burden; Xenograft Model; antitumor agent; base; chemotherapy; inhibitor/antagonist; insight; mTOR protein; mortality; mouse model; neurofibroma; novel; preclinical study; prevent; therapeutic target; tumor; tumor growth; tumor initiation

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. PUBLIC HEALTH RELEVANCE: Benign and malignant peripheral nerve sheath tumors (PNST) are major sources of NF1-associated morbidity and mortality. 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.

描述（由申请人提供）：1型神经纤维瘤病（NF 1）的标志性特征是周围神经系统（PNS）中出现多发性良性周围神经鞘瘤（PNST），也称为神经纤维瘤。一种神经纤维瘤亚型，丛状神经纤维瘤，可以出现在功能关键的神经和弥漫性浸润通过神经，导致神经系统的问题，只有很少可以通过手术治愈。此外，丛状神经纤维瘤是唯一有可能发生恶性转化并进展为恶性外周神经鞘瘤（MPNST）的神经纤维瘤亚型。MPNST是NF1患者死亡的主要原因，特别是对于年龄小于40岁的患者。这些PNS癌症对常规化疗和放疗具有抗性。此外，典型的身体深部位置和局部侵入性生长通常阻止MPNST的完全手术切除。因此，所有年龄段NF1和MPNST的5年生存率都很低，约为21%。总之，这些临床观察强调了对新疗法的迫切需要，该疗法基于对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。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，概括了人类PNST的进行性。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发展的最早阶段。根据我们的初步数据，我们假设，哺乳动物雷帕霉素复合物1（mTORC 1）的活性并不总是升高，而是动态调节在启动，进展和恶性转化的PNST。该提案的目的是系统地研究mTORC 1信号传导的作用和雷帕霉素在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，可以在最早阶段靶向丛状神经纤维瘤和MPNST。具体而言，我们将（1）确定在外周神经鞘肿瘤发展的早期阶段抑制mTORC 1信号传导的表型后果，（2）确定动态调节的mTORC 1活性在外周神经鞘肿瘤发展中的作用。这一建议不仅将提供重要的见解mTORC1介导的信号通路在PNST发展的各个阶段的作用，而且将系统地评估雷帕霉素在PNST的起始，进展和恶性转化的治疗效果。 公共卫生相关性：良性和恶性外周神经鞘瘤（PNST）是NF1相关发病率和死亡率的主要来源。这一建议不仅将提供重要的见解mTORC1介导的信号通路在PNST发展的各个阶段的作用，而且将系统地评估雷帕霉素在PNST的起始，进展和恶性转化的治疗效果。