Effects of mTOR inhibitors on MM tumors

描述（由申请人提供）： 多发性骨髓瘤的特征在于恶性浆细胞浸润到骨髓中，并且其占所有恶性肿瘤的约1%和恶性血液肿瘤的>10%。尽管最近在常规和高剂量化疗方面取得了进展，但MM基本上仍然无法治愈。MM中的重要信号传导途径是PI 3 K/AKT/mTOR信号传导途径。本项目的主要目的是为使用mTOR抑制剂作为多发性骨髓瘤的化疗靶点提供依据。目的包括使用生理学相关的播散性骨髓异种移植模型来研究VEGF和血管生成对用mTOR抑制剂治疗的肿瘤的生长和存活的作用。此外，将测试过度活跃的AKT在MM细胞对雷帕霉素类似物诱导的缺氧和细胞凋亡敏化中调节VEGF内部核糖体进入位点（IRES）功能的能力。还将尝试鉴定和表征调节对mTOR抑制剂敏感性的IRES-反式激活因子（ITAF）。这些具体目标建立在我们先前研究mTOR抑制剂的抗骨髓瘤作用的工作基础上，并将促进我们对AKT对IRES介导的“故障安全”蛋白质翻译途径的调节作用的理解。这些研究是重要的，因为它们的骨髓龛提供了促生存和促血管生成的信号，移植的肿瘤细胞，有助于病理和几乎普遍的化疗耐药性，这种不治之症。

DESCRIPTION (provided by applicant): Multiple myeloma is characterized by infiltration of malignant plasma cells into the bone marrow and which accounts for ~1% of all malignancies and >10% of malignant hematological neoplasms. Despite recent advances in conventional and high-dose chemotherapies, MM remains essentially incurable. An important signaling pathway in MM is the PI3K/AKT/mTOR signaling pathway. The main objective of this project is to provide a rationale for the use of mTOR inhibitors as a chemotherapeutic target against multiple myeloma. The aims include using physiologically relevant disseminated bone marrow xenograft models to study the role of VEGF and angiogenesis on the growth and survival of tumors treated with mTOR inhibitors. In addition, the ability of hyperactive AKT to regulate VEGF internal ribosome entry site (IRES) function in sensitizing MM cells to hypoxia and apoptosis induced by rapalogs will be tested. The identification and characterization of IRES-trans activating factors (ITAFs) that regulate sensitivity to mTOR inhibitors will also be attempted. These specific aims build upon the foundation of our previous work studying the anti-myeloma effects of mTOR inhibitors and will advance our understanding of AKT's regulatory role on the IRES-mediated "fail safe" protein translation pathway. These studies are significant because they bone marrow niche provides pro-survival and pro-angiogenic signals to the engrafted tumor cells that contribute to the pathology and almost universal chemotherapy resistance of this incurable disease.