Use of CCI-779 in multiple myeloma

描述（由申请人提供）：多发性骨髓瘤（MM）患者在初始治疗后复发或初始治疗难治性时预后较差。我们的初步体外和体内（小鼠）数据表明，雷帕霉素（mTOR）抑制剂CCI-779的哺乳动物靶点可能是这些MM患者的有效治疗方法。MM细胞通常含有过度活跃的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，我们的研究表明，尽管mTOR抑制剂单独使用时可诱导MM细胞G1停滞，但与地塞米松联合使用时可引起MM细胞显著程度的凋亡。因此，我们提出了一项I-II期研究，测试CCI-779联合地塞米松对MM患者的毒性和疗效。该研究将提出的一个关键问题是，什么剂量的CCI- 779对患者MM细胞mTOR产生最佳抑制作用。这将通过分析易接近的外周血细胞和骨髓恶性浆细胞对p70S6激酶活性（mTOR的下游底物）的影响来回答。其他需要解决的科学问题是对CCI-779的反应与MM分子特征之间的潜在相关性。总的来说，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的见解，特别是为抗骨髓瘤提供额外的有效药物。CCI-779是一种新的mTOR抑制剂药物，对某些类型的癌症具有潜在的治疗作用。目前的项目是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外的其他恶性肿瘤，从而为如何最好地使用该药物提供见解。

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.