Targeting of DEPTOR in Multiple Myeloma

DEPTOR 在多发性骨髓瘤中的靶向作用

• 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
• 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

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是一种潜在的分子靶点，可用于治疗 多发性骨髓瘤。它在这种疾病中特异性上调，它的沉默对骨髓瘤细胞是致命的。我们, 从而在高通量药物筛选中确定了一种潜在的DEPTOR抑制剂。这种抑制剂对 具有预期的分子改变和诱导死亡的骨髓瘤细胞。在这份提案中，我们计划 进一步开发这种抑制剂。我们将产生生化衍生品，目的是增强 DEPTOR抑制剂的治疗指数，确定抑制剂第一次结合的作用机制 骨髓瘤细胞，确定DEPTOR表达缺失的小鼠对正常组织的可能毒性 评估与临床上使用的其他抗骨髓瘤治疗药物的可能相互作用。我们还将测试 DEPTOR对戊糖磷酸分流系统通量的影响。我们的预期是这些新药 将是骨髓瘤患者使用的医疗器械的重要补充，而且，它们将是 专为具有高DEPTOR表达的肿瘤患者量身定做。