Use of CCI-779 in multiple myeloma

CCI-779 在多发性骨髓瘤中的用途

• 批准号: 7382380
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382380
• 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; Class; 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; Mammalian Cell; 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; Sirolimus; Surrogate Markers; Therapeutic; Thinking; Time; Toxic effect; Toxicity Tests; Translations; Untranslated Regions; Vascular Endothelial Growth Factors; Work; c-myc Genes; cancer type; clinical efficacy; design; in vivo; inhibitor/antagonist; insight; killings; 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其疾病对初始治疗难治，则预后不良。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蛋白（mTOR）抑制剂CCI-779可能是这些MM患者的有效治疗。MM细胞通常含有过度活跃的mTOR、D-细胞周期蛋白、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抑制剂单独使用时诱导MM细胞G1期阻滞，但当与地塞米松联合使用时，它们会引起显著程度的MM细胞凋亡。因此，我们提出了一项I-II期研究，测试CCI-779联合地塞米松治疗MM患者的毒性和疗效。研究中提出的一个关键问题是CCI- 779的剂量对患者的MM细胞mTOR产生最佳抑制作用。这将通过分析对易接近的外周血细胞和骨髓恶性浆细胞中p70 S6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对CCI-779的反应与MM的分子特征之间的潜在相关性。希望这些结果将为CCI-779作为抗癌药物的未来发展提供重要见解，特别是为抗骨髓瘤药物增加额外的有效药物。CCI-779是一种新的mTOR抑制剂药物，具有对抗某些类型癌症的潜力。目前在多发性骨髓瘤患者中的项目旨在了解如何在癌症患者中最好地使用这种药物。因此，预计研究结果将对一般公共卫生有益，因为它们可以外推到除多发性骨髓瘤外的其他恶性肿瘤，从而为如何最好地使用这种药物提供见解。