Targeting of DEPTOR in Multiple Myeloma

DEPTOR 在多发性骨髓瘤中的靶向作用

基本信息

批准号：
9335141
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：
2012-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9335141
关键词：
8q24 Address Adverse effects Apoptosis Regulation Gene Autophagocytosis Binding Binding Proteins Biochemical Cells Cessation of life Chromosomes Clinic Complex Cyclin D1 Data Disease Elderly FRAP1 gene Future Gene Expression Genetic Transcription Glycolysis Growth Hybrids Inhibition of Apoptosis Lead Life Malignant Neoplasms Molecular Multiple Myeloma Mus Normal tissue morphology Paralysed Patients Pentosephosphate Pathway Pharmaceutical Preparations Phosphotransferases Play Population Preclinical Drug Evaluation Proteasome Inhibitor Proteins Regulation Resistance Role TP53 gene Testing Therapeutic Therapeutic Index Therapeutic Uses Toxic effect Up-Regulation Veterans Work Yeasts bcl-1 Genes cytotoxic design drug modification drug testing expectation gene induction in vivo inhibitor/antagonist knock-down mTOR Inhibitor male metabolic profile molecular targeted therapies negative affect neoplastic cell novel therapeutics prevent protein expression response synergism therapeutic target tumor tumorigenesis

项目摘要

Preliminary work indicates the mTOR-binding protein DEPTOR is a potential molecular target for therapy in multiple myeloma. It is specifically upregulated in this disease and its silencing is lethal to myeloma cells. We, thus, identified a potential DEPTOR inhibitor in a high-throughput drug screen. The inhibitor is effective in myeloma cells with the expected molecular alterations and induction of death. In this proposal we plan to further develop this inhibitor. We will generate biochemical derivatives with the aim of enhancing the therapeutic index of DEPTOR inhibitors, identify the mechanism of action of where the inhibitors first bind in myeloma cells, ascertain possible toxicity to normal tissues in mice with deleted DEPTOR expression and assess possible interactions with other anti-myeloma therapeutics that are used in the clinic. We will also test the effect of DEPTOR on flux through the pentose phosphate shunt. Our expectation is that these new drugs will be important additions to the armamentarium used in myeloma patients and, furthermore, they will be specifically tailored to patients with tumors that have high DEPTOR expression.

初步工作表明 mTOR 结合蛋白 DEPTOR 是治疗以下疾病的潜在分子靶点多发性骨髓瘤。它在这种疾病中特别上调，并且它的沉默对于骨髓瘤细胞来说是致命的。我们，因此，在高通量药物筛选中鉴定出一种潜在的 DEPTOR 抑制剂。该抑制剂有效地骨髓瘤细胞具有预期的分子改变和诱导死亡。在本提案中，我们计划进一步开发这种抑制剂。我们将生产生化衍生物，旨在增强 DEPTOR 抑制剂的治疗指数，确定抑制剂首先结合的作用机制骨髓瘤细胞，确定 DEPTOR 表达缺失的小鼠对正常组织可能的毒性，以及评估与临床使用的其他抗骨髓瘤治疗药物可能存在的相互作用。我们也会测试 DEPTOR 对通过磷酸戊糖分路的通量的影响。我们的期望是这些新药将成为骨髓瘤患者使用的医疗设备的重要补充，而且，它们将专门针对具有高 DEPTOR 表达的肿瘤患者。