Effects of mTOR inhibitors on multiple myeloma tumors

描述(由申请人提供)：AKT信号通路对多发性骨髓瘤细胞(MM)的生存很重要。AKT的一个重要下游靶点是哺乳动物的雷帕霉素靶点(MTOR)，它介导p70和4E-BP1的磷酸化，这两个因子分别负责核糖体的生物发生和帽依赖蛋白的翻译。针对mTOR的药物，如雷帕霉素，可以抑制关键蛋白的帽依赖翻译，导致细胞周期停滞和细胞凋亡。大量研究表明，对mTOR抑制剂的抗肿瘤作用的敏感性与AKT活性的增强有关，我们假设这是因为具有过度活跃的AKT功能的细胞依赖于mTOR介导的帽依赖的生存所需蛋白质的翻译。在这些“高”AKT细胞中，我们预计mTOR抑制剂可以阻止这些蛋白的帽依赖翻译，导致细胞周期停滞和细胞凋亡。相反，具有“低”AKT功能的MM细胞可能利用非AKT/mTOR依赖(即帽不依赖)的翻译途径来表达这些关键蛋白，使它们对mTOR抑制具有抵抗力。帽不依赖的挽救途径是由位于特定mRNA5‘端非编码区的内部核糖体进入位点(IRESes)介导的。为了支持这一假说，我们最近证明了具有已知IRES序列的蛋白质(例如c-myc、VEGF)的翻译在AKT MM细胞中的高表达和低表达是不同的。 因此，这一应用将测试AKT介导的MM细胞对mTOR抑制剂的敏感性是否是由于在体外和体内抑制了关键生存的帽非依赖性翻译挽救途径和血管生成蛋白。威尔还将测试调控帽子非依赖性翻译的潜在机制(S)是否通过这些基因转录本的IRES功能来调节。这款K01应用程序将专门为私家侦探在其职业生涯的关键时期提供科学、学术和职业发展方面的指导培训，并将促进他向癌症生物学领域的独立调查员过渡。

DESCRIPTION (provided by applicant): The AKT signaling pathway is important for the survival of multiple myeloma cells (MM). An important downstream target of AKT is the mammalian target of rapamycin (mTOR), which mediates phosphorylation of p70 and 4E-BP1, factors responsible for ribosome biogenesis and cap-dependent protein translation, respectively. Drugs that target mTOR, such as rapamycin, inhibit cap-dependent translation of critical proteins, resulting in cell cycle arrest and apoptosis. Numerous studies have demonstrated that the sensitivity to the anti-tumor effects of mTOR inhibitors correlates to heightened AKT activity, and we hypothesize that this is because cells with hyperactive AKT function depend upon mTOR-mediated cap-dependent translation of proteins required for survival. In these "high" AKT cells, we expect that Mtor inhibitors block cap-dependent translation of these proteins, leading to cell cycle arrest and apoptosis. In contrast, MM cells with "low" AKT function may utilize non-AKT/mTOR-dependent (i.e. cap-independent) translational pathways to express these critical proteins, making them resistant to mTOR inhibition. The cap-independent salvage pathway is mediated by internal ribosome entry sites (IRESes) located in the 5'UTR of specific mRNAs. In support of this hypothesis, we have recently demonstrated that translation of proteins with known IRES sequences (e.g. c-myc, VEGF) are differently expressed "high" versus "low" AKT MM cells. Therefore, this application will test whether AKT-mediated sensitivity of MM cells to mTOR inhibitors is due to inhibition of the cap-independent translation salvage pathways of critical survival and angiogenic proteins in vitro and in vivo. Will will also test whether the underlying mechanism(s) regulating cap-independent translation is mediated through IRES function of these gene transcripts. This K01 application will specifically provide mentored scientific, academic and career development training to the P.I. during a crucial period in his career and will facilitate his transition to an independent investigator in the field cancer biology.