Effects of mTOR inhibitors on MM tumors

mTOR 抑制剂对 MM 肿瘤的影响

• 批准号: 8245602
• 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/8245602
• 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

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. PUBLIC HEALTH RELEVANCE: Multiple myeloma is an incurable disease of the bone marrow that is resistant to treatment therapies. The main focus of this project is to test whether drugs that inhibit the mTOR pathway can kill myeloma tumors in vivo and what are the underlying mechanism(s) responsible for this in the tumor microenvironment. These studies will have significant clinical relevance to the Veteran population, since occurs most commonly in black males over the age of 65 (64.5/100,000), a major proportion of the Veteran population.

描述（由申请人提供）： 多发性骨髓瘤的特征是恶性浆细胞浸润骨髓，约占所有恶性肿瘤的 1%，占恶性血液肿瘤的 10% 以上。尽管最近在传统和大剂量化疗方面取得了进展，但多发性骨髓瘤基本上仍然无法治愈。 MM 中的一个重要信号通路是 PI3K/AKT/mTOR 信号通路。该项目的主要目标是为使用 mTOR 抑制剂作为多发性骨髓瘤的化疗靶点提供理论依据。目的包括使用生理相关的播散性骨髓异种移植模型来研究 VEGF 和血管生成对 mTOR 抑制剂治疗的肿瘤生长和存活的作用。此外，还将测试过度活跃的 AKT 调节 VEGF 内部核糖体进入位点 (IRES) 功能的能力，从而使 MM 细胞对 Rapalogs 诱导的缺氧和细胞凋亡敏感。还将尝试鉴定和表征调节 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之前研究 mTOR 抑制剂的抗骨髓瘤作用的基础上，并将增进我们对 AKT 对 IRES 介导的“故障安全”蛋白翻译途径的调节作用的理解。这些研究意义重大，因为它们的骨髓生态位向移植的肿瘤细胞提供促生存和促血管生成信号，从而导致这种不治之症的病理学和几乎普遍的化疗耐药性。 公共卫生相关性： 多发性骨髓瘤是一种无法治愈的骨髓疾病，对治疗方法有抵抗力。该项目的主要重点是测试抑制 mTOR 通路的药物是否可以在体内杀死骨髓瘤肿瘤，以及肿瘤微环境中造成这种情况的潜在机制是什么。这些研究将与退伍军人群体具有重要的临床相关性，因为这种情况最常见于 65 岁以上的黑人男性 (64.5/100,000)，他们是退伍军人群体的主要比例。