Elucidating the role of the mTOR pathway in NF1-related tumorigenesis

描述（由申请人提供）：已知NF 1编码的蛋白质神经纤维蛋白在生物化学上作为Ras-GTP酶激活蛋白（RasGAP）发挥作用超过15年。然而，尽管有这些知识，但对疾病发病机制中涉及的关键下游效应途径知之甚少。我们最近证明，mTOR，一种与多种家族性癌症综合征的发展有关的激酶，在对NF 1突变的反应中严重失调。此外，我们已经证明NF 1缺陷型肿瘤细胞对mTOR抑制剂高度敏感，新的初步研究表明这些抑制剂可有效抑制小鼠肿瘤的生长。该提案的中心目标是阐明mTOR通路在NF 1相关肿瘤发生中的重要性。我们在原代Nf 1缺陷小鼠细胞、人肿瘤细胞系和基因工程小鼠模型中的初步数据表明，该途径对肿瘤发生过程有重要贡献。因此，本提案的目的之一是使用各种小鼠模型来确定雷帕霉素（一种mTOR抑制剂）是否代表NF 1的可行疗法。然而，虽然mTOR抑制剂可能是治疗上有用的药物，但我们还旨在定义该途径的其他组分。特别是，我们打算鉴定在mTOR上游或下游起作用的其他激酶，因为它们是小分子抑制剂的潜在靶点。这些研究不仅有助于我们理解NF 1的发病机制，也将影响未来治疗的发展。具体来说，如果我们能够证明雷帕霉素在MPNST小鼠模型中是一种有效的药物，这些数据应该会刺激未来的临床试验。此外，在这种情况下，通过机械解剖mTOR通路，我们可能会发现其他治疗候选者。这些信息应该提供深入了解NF 1以及Ras通路失调的其他癌症的发病机制。

DESCRIPTION (provided by applicant): The NF1-encoded protein, neurofibromin, has been known to biochemically function as a Ras-GTPase activating protein (RasGAP) for over fifteen years. However, despite this knowledge little is known about the critical downstream effector pathways involved in disease pathogenesis. We have recently demonstrated that mTOR, a kinase implicated in the development of a variety of familial cancer syndromes, is critically deregulated in response to NF1 mutations. Moreover, we have shown that NF1-deficient tumor cells are highly sensitive to mTOR inhibitors, and newer preliminary studies suggest that these inhibitors are effective in inhibiting the growth of tumors in mice. The central goal of this proposal is to elucidate the importance of the mTOR pathway in NF1-associated tumorigenesis. Our preliminary data in primary Nf1-deficient mouse cells, human tumor cell lines, and a genetically engineered mouse model, suggest that this pathway critically contributes to the tumorigenic process. Therefore one of the Aims of this proposal is designed to determine whether rapamycin, an mTOR inhibitor, represents a viable therapy for NF1, using various mouse models. However, while mTOR inhibitors are likely to be therapeutically useful agents, we also aim to define additional components of this pathway. In particular, we intend to identify other kinases that function upstream or downstream of mTOR, as they are potential targets for small molecule inhibitors. These studies will not only contribute to our understanding of NF1 pathogenesis but will also impact the development of future therapies. Specifically, if we are able to demonstrate that rapamycin is an effective agent in mouse models of MPNST, these data should stimulate future clinical trials. Moreover, by mechanistically dissecting the mTOR pathway in this context we are likely to identify additional therapeutic candidates. This information should provide insight into the pathogenesis of NF1 as well as other cancers in which the Ras pathway is deregulated.