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: 8246412
• 负责人: YUAN ZHU
• 金额: $ 34.02万
• 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/8246412
• 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; public health relevance; 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(申请人提供)：1型神经纤维瘤病(NF1)的显著特征是周围神经系统(PNS)发生多发性良性周围神经鞘瘤(PNST)，也称为神经纤维瘤。神经纤维瘤的一种亚型，丛状神经纤维瘤，可出现在功能关键的神经中，并弥漫性地渗透到神经中，导致神经问题，只有极少数情况下才能通过手术治愈。此外，丛状神经纤维瘤是唯一有可能发生恶性转化和进展为恶性周围神经鞘瘤(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40岁以下的人。这些PNS癌症对传统的化疗和放射治疗具有耐药性。此外，典型的体内深部位置和局部侵袭性生长往往阻碍了MPNSTs的完全手术切除。因此，患有NF1和MPNSTs的所有年龄段的5年存活率都很低，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MPNSTs基础的分子和细胞机制的更好的理解来进行新的治疗。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(S)的作用和抗肿瘤药物(S)在PNST发展的各个阶段的疗效。特别是，我们已经在PNST发育的早期阶段确定了关键的细胞和分子事件。根据我们的初步数据，我们假设哺乳动物雷帕霉素复合体1的靶点(MTORC1)活性并不总是升高，而是在PNST的启动、进展和恶变过程中动态调节。本研究的目的是系统研究mTORC1信号通路在PNST的发生、发展和恶变中的作用以及雷帕霉素的治疗作用。这些研究旨在确定可以在早期阶段针对丛状神经纤维瘤和MPNST的潜在治疗窗口。具体地说，我们将(1)确定在周围神经鞘肿瘤发展的早期阶段抑制mTORC1信号的表型后果，以及(2)确定动态调节的mTORC1活性在周围神经鞘肿瘤发展中的作用。这一建议不仅将为mTORC1介导的信号通路在PNST发展的各个阶段中的作用提供重要的见解，而且还将系统地评估雷帕霉素在PNST的发生、发展和恶变中的治疗作用。 公共卫生相关性：良性和恶性周围神经鞘瘤(PNST)是NF1相关发病率和死亡率的主要来源。这一建议不仅将为mTORC1介导的信号通路在PNST发展的各个阶段中的作用提供重要的见解，而且还将系统地评估雷帕霉素在PNST的发生、发展和恶变中的治疗作用。