Effects of mTOR inhibitors on MM tumors

mTOR 抑制剂对 MM 肿瘤的影响

• 批准号: 8598067
• 负责人: Patrick J Frost
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598067
• 关键词: AKT inhibition; Accounting; Active Sites; Address; Apoptosis; Apoptotic; Area; B lymphoid malignancy; Biological Markers; Bone Marrow; Bone Marrow Diseases; CCI-779; Cell Death; Cell Line; Cell Survival; Cells; Clinical Trials; Disease; Down-Regulation; Effectiveness; Elderly; Foundations; G1 Arrest; Growth; Hematologic Neoplasms; High Dose Chemotherapy; Home environment; Hypersensitivity; Hypoxia; Hypoxia Inducible Factor; In Vitro; Infiltration; Internal Ribosome Entry Site; Malignant - descriptor; Malignant Neoplasms; Mantle Cell Lymphoma; Mediating; Modeling; Molecular; Multiple Myeloma; Mus; Outcome; PI3K/AKT; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Plasma Cells; Play; Population; Protein Biosynthesis; Protein Translation Pathway; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Resistance; Role; Signal Pathway; Signal Transduction; Sirolimus; Skeleton; Testing; Transgenes; Translations; Vascular Endothelial Growth Factors; Veterans; Waldenstrom' s disease; Work; Xenograft Model; angiogenesis; antitumor agent; bone marrow xenograft; chemotherapy; clinically relevant; design; in vivo; inhibitor/antagonist; innovation; killings; mTOR protein; male; neoplastic cell; prevent; research study; resistance mechanism; response; tumor; tumor microenvironment

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.

描述（由申请人提供）： 多发性骨髓瘤的特征是恶性血浆细胞浸入骨髓中，占所有恶性肿瘤的约1％，> 10％的恶性血液肿瘤。尽管传统和高剂量化学疗法最近取得了进步，但MM仍无法治愈。 MM中重要的信号通路是PI3K/AKT/MTOR信号通路。该项目的主要目的是为使用MTOR抑制剂作为针对多发性骨髓瘤的化学治疗靶靶标提供基本原理。目的包括使用生理相关的散布骨髓异种移植模型来研究VEGF和血管生成对用MTOR抑制剂治疗的肿瘤生长和存活的作用。此外，将测试过度活跃AKT调节VEGF内部核糖体入口位点（IRES）功能在使MM细胞对低氧和甲壳虫诱导的凋亡敏感的能力中。还将尝试鉴定和表征IRES-TRANS激活因子（ITAF）调节对MTOR抑制剂敏感性的识别和表征。这些具体目标是基于我们先前研究MTOR抑制剂抗肌瘤作用的基础，并将促进我们对AKT对IRES介导的“失败安全”蛋白质翻译途径的调节作用的理解。这些研究之所以重要，是因为它们骨髓生态位为植入的肿瘤细胞提供了促生存和亲血管生成信号，这些信号有助于这种无法治愈的疾病的病理和几乎普遍的化学疗法抗性。