Enhancing the mTOR-targeted cancer therapy

描述（由申请人提供）：靶向癌症治疗代表了我们对抗癌症的重大进展。我们研究的长期目标是基于我们对癌症生物学的机制研究，开发出新颖有效的癌症治疗方案。目前的应用专门针对提高mTOR（雷帕霉素的哺乳动物靶点）靶向癌症治疗的疗效。雷帕霉素及其衍生物特异性抑制mTOR信号传导，目前正积极地在i -ll期肿瘤临床试验中单独或与其他药物联合进行测试。活化的mTOR导致p70s6激酶（p70S6K）和真核翻译起始因子4E （elF4E）结合蛋白1 （4E- bp1）的磷酸化，并随后增强mrna的翻译。因此，p70S6K和4E-BP1的磷酸化状态已被广泛用作mTOR抑制剂的功能读数。然而，我们的初步研究揭示了一个令人兴奋的新发现，雷帕霉素抑制mTOR可迅速增加Akt和elF4E的磷酸化，同时抑制p70S6K和4E-BP1的磷酸化。这些诱导的Akt和elF4E的激活似乎抵消了雷帕霉素诱导的mTOR抑制作用。因此，这些新发现可能为改进mtor靶向癌症治疗提供新的机会。我们的研究结果导致以下假设：1)抑制mTOR通过可能涉及蛋白磷酸酶2A （PP2A）的机制激活PI3K/Akt通路；2) mTOR抑制剂通过PI3K/ akt介导的机制增加elF4E磷酸化；3)激活PI3K/Akt和elF4E会抵消mTOR抑制剂的抗癌功效，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的同时引起PI3K/Akt激活（特异性目标1）并增加elF4E磷酸化（特异性目标2）。此外，我们将测试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（特异性目的3）。本研究的完成将揭示mTOR负调控包括elF4E在内的PI3K/Akt通路的新的生物学途径或范式，并为增强mTOR靶向癌症治疗提供新的策略，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.