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：
8963450
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/8963450
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 EIF4EBP1 gene Elderly Evaluation Event FRAP1 gene Feedback Future G1 Arrest Generations Growth Hybrids In Vitro Institutes Life MAP Kinase Gene Malignant Neoplasms Marrow Mediating Molecular Multiple Myeloma Multiprotein Complexes 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 improved inhibitor/antagonist mTOR Inhibitor male migration mouse model 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激酶在两个多蛋白络合物TORC1和TORC2中起作用，是促进蛋白质的肿瘤。我们将使用酵母2-杂化筛选来识别可以中断MTOR与TORC2复合物中MTOR结合的化合物，因为MTORC2功能所需的这种结合对于多发性骨髓瘤肿瘤细胞的生长和存活似乎至关重要。这些化合物将进一步测试和开发，作为可能的抗肌瘤药物。这需要评估其分子作用和体外细胞作用在明确定义的骨髓瘤细胞系和从患者骨髓获得的原发性肿瘤细胞制剂中的评估。我们还将确定化合物在骨髓瘤生长的异种移植鼠模型中的抗肌瘤疗效。此外，我们还将确定TORC2的临界底物，当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。