Effects of mTOR inhibitors on multiple myeloma tumors

描述（由申请人提供）：AKT信号通路对于多发性骨髓瘤细胞（MM）的存活非常重要。AKT的一个重要下游靶标是雷帕霉素的哺乳动物靶标（mTOR），其介导p70和4 E-BP 1的磷酸化，p70和4 E-BP 1分别是负责核糖体生物合成和帽依赖性蛋白翻译的因子。靶向mTOR的药物，如雷帕霉素，抑制关键蛋白的帽依赖性翻译，导致细胞周期停滞和凋亡。许多研究已经证明，对mTOR抑制剂的抗肿瘤作用的敏感性与AKT活性升高相关，我们假设这是因为具有过度活跃的AKT功能的细胞依赖于存活所需的mTOR介导的帽依赖性蛋白质翻译。在这些“高”AKT细胞中，我们预期Mtor抑制剂阻断这些蛋白质的帽依赖性翻译，导致细胞周期停滞和凋亡。相反，具有“低”AKT功能的MM细胞可以利用非AKT/mTOR依赖性（即帽非依赖性）翻译途径来表达这些关键蛋白，使其对mTOR抑制具有抗性。帽非依赖性补救途径由位于特定mRNA的5 'UTR中的内部核糖体进入位点（IRES）介导。为了支持这一假设，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“高”与“低”AKT MM细胞中不同地表达。 因此，本申请将测试AKT介导的MM细胞对mTOR抑制剂的敏感性是否是由于体外和体内关键存活和血管生成蛋白的帽非依赖性翻译补救途径的抑制。Will还将测试调节帽非依赖性翻译的潜在机制是否通过这些基因转录物的IRES功能介导。此K 01应用程序将专门为PI提供指导性的科学，学术和职业发展培训。在他职业生涯的关键时期，将有助于他过渡到癌症生物学领域的独立研究者。

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.