Use of CCI-779 in multiple myeloma

描述(申请人提供)：多发性骨髓瘤(MM)患者一旦在初始治疗后复发，或者他们的疾病对初始治疗无效，预后就很差。我们在体外和体内(小鼠)的初步数据表明，雷帕霉素(MTOR)抑制剂的哺乳动物靶点CCI-779可能是治疗这些MM患者的有效药物。MM细胞通常含有高活性的mTOR、D-Cyclins、c-myc和AKT，所有这些都提示可能对mTOR抑制剂敏感。此外，我们的工作表明，尽管mTOR抑制剂单独使用时会导致MM细胞G1期停滞，但当它们与地塞米松联合使用时，会引起显著程度的MM细胞凋亡。因此，我们建议进行一项I-II期研究，测试CCI-779联合地塞米松治疗多发性骨髓瘤患者的毒性和疗效。这项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产生最佳抑制效果。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p70S6激酶活性(mTOR下游底物)的影响来回答。其他有待解决的科学问题是对CCI-779的反应与MM的分子特征之间的潜在相关性。希望这些结果将在总体上为CCI-779作为抗癌剂的未来发展提供重要的见解，特别是为抗骨髓瘤的武器库增加一种额外的有效药物。CCI-779是一种新的mTOR抑制剂药物，具有治疗某些类型癌症的潜力。目前的项目是针对多发性骨髓瘤患者，旨在了解如何最好地在癌症患者中使用这种药物。因此，预计这项研究的结果将有益于公众健康，因为它们可以推断为多发性骨髓瘤以外的其他恶性肿瘤，从而为如何最好地使用这种药物提供了洞察力。

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.