Effects of mTOR inhibitors on multiple myeloma tumors

mTOR抑制剂对多发性骨髓瘤的影响

• 批准号: 6983303
• 负责人: Patrick J Frost
• 金额: $ 12.8万
• 依托单位: BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6983303
• 关键词: SCID mouse; apoptosis; biological signal transduction; cell cycle; genetic transcription; genetic translation; inhibitor /antagonist; messenger RNA; multiple myeloma; neoplasm /cancer genetics; phosphorylation; sirolimus

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.

描述（由申请人提供）：AKT 信号通路对于多发性骨髓瘤细胞 (MM) 的存活很重要。 AKT 的一个重要下游靶标是哺乳动物雷帕霉素靶标 (mTOR)，它介导 p70 和 4E-BP1 的磷酸化，这两个因子分别负责核糖体生物发生和帽依赖性蛋白翻译。雷帕霉素等靶向 mTOR 的药物可抑制关键蛋白的帽依赖性翻译，从而导致细胞周期停滞和细胞凋亡。大量研究表明，mTOR 抑制剂抗肿瘤作用的敏感性与 AKT 活性增强相关，我们推测这是因为 AKT 功能亢进的细胞依赖于 mTOR 介导的帽依赖型生存所需蛋白质翻译。在这些“高”AKT 细胞中，我们预计 Mtor 抑制剂会阻断这些蛋白质的帽依赖性翻译，从而导致细胞周期停滞和细胞凋亡。相反，AKT 功能“低”的 MM 细胞可能利用非 AKT/mTOR 依赖性（即 cap 独立性）翻译途径来表达这些关键蛋白，从而使其对 mTOR 抑制具有抵抗力。不依赖帽的挽救途径由位于特定 mRNA 5'UTR 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，具有已知 IRES 序列的蛋白质（例如 c-myc、VEGF）的翻译在“高”AKT MM 细胞和“低”AKT MM 细胞中表达不同。 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独立翻译挽救途径的抑制所致。 Will 还将测试调节帽独立翻译的潜在机制是否是通过这些基因转录本的 IRES 功能介导的。该 K01 申请将专门为 P.I. 提供受指导的科学、学术和职业发展培训。在他职业生涯的关键时期，这将有助于他过渡到癌症生物学领域的独立研究者。