Targeting TORC2 in Multiple Myeloma

多发性骨髓瘤中的 TORC2 靶向治疗

基本信息

批准号：
8762435
负责人：
ALAN K LICHTENSTEIN
金额：
--
依托单位：
VA GREATER LOS ANGELES HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-10-01 至 2016-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8762435
关键词：
Active Sites Address Adhesions Apoptosis Apoptotic Binding Binding Sites Bone Marrow Cell Cycle Cell Cycle Arrest Cell Cycle Proteins Cell Line Cell Survival Cell-Cell Adhesion Cells Complex Cytostatics Data Development Disease Elderly Evaluation Event Feedback Future G1 Arrest Generations Growth Hybrids In Vitro Institutes Life MAP Kinase Gene Malignant Neoplasms Marrow Mediating Modeling Molecular Multiple Myeloma Multiprotein Complexes Mus New Agents PI3K/AKT Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Phosphotransferases Population Primary Neoplasm Proteins Proto-Oncogene Proteins c-akt Raptors Resistance Signal Transduction Sirolimus Site Skeleton Tacrolimus Binding Protein 1A Testing Therapeutic Translations Veterans Work Xenograft procedure Yeasts cell motility cell preparation design human FRAP1 protein improved inhibitor/antagonist mTOR Inhibitor male migration neoplastic cell novel pre-clinical prevent protein complex research study resistance mechanism screening tumor yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): The mTOR kinase functions in two multiprotein complexes, TORC1 and TORC2, and is a tumor promoting protein. We will use a yeast-2-hybrid screen to identify compounds that can interrupt binding of mTOR to its partners within the TORC2 complex as this binding is required for mTORC2 function and appears critical for growth and survival of multiple myeloma tumor cells. These compounds will be further tested and developed as possible anti-myeloma agents. This entails assessment of their molecular effects and in vitro cellular effects in well defined myeloma cell lines and primary tumor cell preparations obtained from bone marrows of patients. We will also identify the compounds' anti-myeloma efficacy in xenograft murine models of myeloma growth. In addition, we will also identify the critical substrates of TORC2 which, when inhibited by our agents, results in apoptosis and inhibited myeloma cell adhesion and migration.

描述（由申请人提供）： mTOR 激酶在两种多蛋白复合物 TORC1 和 TORC2 中发挥作用，是一种肿瘤促进蛋白。我们将使用酵母 2 杂交筛选来鉴定可以中断 mTOR 与其 TORC2 复合物内伙伴结合的化合物，因为这种结合是 mTORC2 功能所必需的，并且对于多发性骨髓瘤肿瘤细胞的生长和存活至关重要。这些化合物将被进一步测试并开发为可能的抗骨髓瘤药物。这需要评估它们在明确的骨髓瘤细胞系和从患者骨髓中获得的原代肿瘤细胞制剂中的分子效应和体外细胞效应。我们还将确定这些化合物在骨髓瘤生长的异种移植鼠模型中的抗骨髓瘤功效。此外，我们还将鉴定 TORC2 的关键底物，当被我们的药物抑制时，会导致细胞凋亡并抑制骨髓瘤细胞粘附和迁移。