Use of CCI-779 in multiple myeloma

CCI-779 在多发性骨髓瘤中的应用

• 批准号: 7666888
• 负责人: ALAN K LICHTENSTEIN
• 金额: $ 32万
• 依托单位: BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7666888
• 关键词: Address; Animal Model; Antineoplastic Agents; Apoptosis; Biological Assay; Blood Cells; Bone Marrow; CCI-779; Cell Cycle Arrest; Cell Cycle Proteins; Cells; Characteristics; Classification; Clinical Trials; Cyclin D1; Cyclins; Cytotoxic agent; DNA; Data; Development; Dexamethasone; Disease; Dose; Down-Regulation; Drug usage; Future; G1 Arrest; General Population; Genetic; Growth Factor; Hand; Hematopoietic; Human; In Vitro; Insulin-Like Growth Factor I; Interleukin-6; Laboratories; Learning; Lesion; Malignant - descriptor; Malignant Neoplasms; Maximum Tolerated Dose; Methylation; Modeling; Molecular; Multiple Myeloma; Mus; Mutation; Non-Malignant; PTEN gene; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phase I/II Trial; Phase II Clinical Trials; Phosphotransferases; Plasma Cells; Proto-Oncogene Proteins c-akt; Protocols documentation; Public Health; Refractory; Relapse; Relative (related person); Resistance; Series; Signal Pathway; Surrogate Markers; Therapeutic; Time; Toxic effect; Toxicity Tests; Translations; Untranslated Regions; Vascular Endothelial Growth Factors; Work; c-myc Genes; cancer type; clinical efficacy; design; effective therapy; in vivo; inhibitor/antagonist; insight; killings; mTOR protein; neoplastic cell; outcome forecast; preclinical study; prevent; promoter; response

DESCRIPTION (provided by applicant): Patients with multiple myeloma (MM) have a poor prognosis once they have relapsed after initial therapy or when their disease is refractory to initial therapy. Our preliminary in vitro and in vivo (mice) data indicate that the mammalian target of rapamycin (mTOR) inhibitor, CCI-779, may be effective therapy in these MM patients. MM cells often contain hyperactive mTOR, D-cyclins, c-myc and AKT, all of which suggest probable sensitivity to mTOR inhibitors. Furthermore, our work suggests that, although mTOR inhibitors induce MM cell G1 arrest when they are used alone, they cause a remarkable degree of MM cell apoptosis when combined with dexamethasone. Thus, we propose a phase I-II study, testing the toxicity and efficacy of CCI-779 combined with dexamethasone in MM patients. A critical question that will be asked in the study is what dose of CCI- 779 produces an optimal inhibitory effect on MM cell mTOR in patients. This will be answered by analyzing effects on p70S6 kinase activity (downstream substrate of mTOR) in easily accessible peripheral blood cells and bone marrow malignant plasma cells. Additional scientific issues to be addressed are the potential correlations between responses to CCI-779 and molecular characteristics of MM. Hopefully, the results will, in general, provide important insight into the future development of CCI-779 as an anti-cancer agent and, in particular, add an additional effective agent to the anti-myeloma armamentarium. CCI-779 is a new mTOR inhibitor drug which has potential against certain types of cancer. The current project, in patients with multiple myeloma, is designed to learn how to best use this drug in patients with cancer. As such, it is anticipated that the results of the study will be of benefit to the general public health in that they can be extrapolated to other malignancies in addition to multiple myeloma and, thus, provide insight in how to best use this drug.

描述（由申请人提供）：多发性骨髓瘤（MM）患者一旦在初始治疗后复发或疾病对初始治疗无效时，预后较差。我们的初步体外和体内（小鼠）数据表明，哺乳动物雷帕霉素靶点 (mTOR) 抑制剂 CCI-779 可能是这些 MM 患者的有效治疗方法。 MM 细胞通常含有高度活跃的 mTOR、D-cyclins、c-myc 和 AKT，所有这些都表明可能对 mTOR 抑制剂敏感。此外，我们的工作表明，虽然 mTOR 抑制剂单独使用时会诱导 MM 细胞 G1 期停滞，但与地塞米松联合使用时，它们会引起显着程度的 MM 细胞凋亡。因此，我们提出一项I-II期研究，测试CCI-779联合地塞米松对MM患者的毒性和疗效。研究中将提出的一个关键问题是，什么剂量的 CCI-779 对患者的 MM 细胞 mTOR 产生最佳的抑制作用。这将通过分析对易于接近的外周血细胞和骨髓恶性浆细胞中 p70S6 激酶活性（mTOR 的下游底物）的影响来回答。需要解决的其他科学问题是 CCI-779 反应与 MM 分子特征之间的潜在相关性。希望这些结果总体上能够为 CCI-779 作为抗癌药物的未来发展提供重要的见解，特别是为抗骨髓瘤药物添加一种额外的有效药物。 CCI-779 是一种新型 mTOR 抑制剂药物，具有对抗某些类型癌症的潜力。目前的项目针对多发性骨髓瘤患者，旨在了解如何在癌症患者中最好地使用这种药物。因此，预计该研究的结果将有益于一般公众健康，因为它们可以外推到除多发性骨髓瘤之外的其他恶性肿瘤，从而提供有关如何最好地使用这种药物的见解。