Enhancing the mTOR-targeted cancer therapy

描述(由申请人提供)：有针对性的癌症治疗代表着我们抗击癌症的重大进步。我们研究的长期目标是在我们对癌症生物学的机理研究的基础上，开发新的、有效的癌症治疗方案。目前的应用特别旨在提高mTOR(雷帕霉素的哺乳动物靶点)靶向癌症治疗的疗效。雷帕霉素及其专门抑制mTOR信号转导的衍生物目前正在进行积极的测试，要么单独测试，要么与其他药物联合测试，进行L-11期肿瘤临床试验。激活的mTOR导致p70 S6激酶(P70S6K)和真核细胞翻译起始因子4E(ElF4E)结合蛋白1(4E-BP1)的磷酸化，从而增强mRNAs的翻译。因此，p70S6K和4E-BP1的磷酸化状态被广泛用作mTOR抑制剂的功能读数。然而，我们的初步研究发现，雷帕霉素抑制mTOR可以迅速增加Akt和elF4E的磷酸化，而抑制p70S6K和4E-BP1的磷酸化。这些对Akt和elF4E的诱导激活似乎抵消了雷帕霉素诱导的mTOR抑制的作用。因此，这些新的发现可能为改进mTOR靶向癌症治疗提供新的机会。我们的发现导致以下假设：1)抑制mTOR激活PI3K/Akt途径的机制可能涉及蛋白磷酸酶2A(PP2A)；2)mTOR抑制剂通过PI3K/Akt介导的机制增加elF4E的磷酸化；3)激活PI3K/Akt和elF4E抵消mTOR抑制剂的抗癌效果，而共同靶向PI3K/Akt/elF4E激活同时抑制mTOR将增强mTOR靶向癌症治疗。为了验证这些假设，我们将确定mTOR抑制剂如何在抑制mTOR的同时导致PI3K/Akt激活(特异性目标1)和增加elF4E磷酸化(特异性目标2)。此外，我们还将测试PI3K/Akt/elF4E激活对mTOR抑制剂介导的人类癌细胞生长抑制的影响(特定目标3)。这一建议的完成将揭示一种新的生物学途径或范式，即mTOR负性调控包括elF4E在内的PI3K/Akt通路，并开发新的策略来加强mTOR靶向癌症治疗，具有直接的临床收获和翻译意义。

DESCRIPTION (provided by applicant): Targeted cancer therapies represent a major advance in our fight against cancer. The long-term goal of our research is to develop novel and efficacious therapeutic regimens for cancer treatment based on our mechanistic studies on cancer biology. The current application aims specifically at enhancing the efficacy of mTOR (the mammalian target of rapamycin)-targeted cancer therapy. Rapamycin and its derivatives that specifically inhibit mTOR signaling are now being actively tested either alone or in combination with other drugs in phase l-ll oncology clinical trials. Activated mTOR leads to phosphorylation of p70 S6 kinase (p70S6K) and eukaryotic translation initiation factor 4E (elF4E) binding protein 1 (4E-BP1), and the subsequently enhanced translation of mRNAs. Thus, the phosphorylation states of p70S6K and 4E-BP1 have been widely used as functional readouts for mTOR inhibitors. However, our preliminary studies have revealed an exciting new finding that inhibition of mTOR by rapamycin rapidly increases phosphorylation of Akt and elF4E while suppressing the phosphorylation of p70S6K and 4E-BP1. These induced activations of Akt and elF4E appear to counteract the action of the rapamycin-induced mTOR inhibition. Thus, these novel findings may provide new opportunities for improving the mTOR-targeted cancer therapy. Our findings lead to the following hypotheses: 1) Inhibition of mTOR activates PI3K/Akt pathway through a mechanism that may involve protein phosphatase 2A (PP2A); 2) an mTOR inhibitor increases elF4E phosphorylation via PI3K/Akt-mediated mechanism; and 3) activation of PI3K/Akt and elF4E counteracts mTOR inhibitors' anticancer efficacy, whereas co-targeting PI3K/Akt/elF4E activation while suppressing mTOR will enhance mTOR-targeted cancer therapy. To test these hypotheses, we will determine how an mTOR inhibitor causes PI3K/Akt activation (specific aim 1) and increases elF4E phosphorylation (specific aim 2) while suppressing mTOR. In addition, we will test the impact of PI3K/Akt/elF4E activation on mTOR inhibitor-mediated growth inhibition of human cancer cells (specific aim 3). The accomplishment of this proposal will reveal a novel biological pathway or paradigm that mTOR negatively regulates PI3K/Akt pathway including elF4E and develop new strategies to enhance the mTOR-targeted cancer therapy with immediate clinical gain and translation significance.