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. ? ? ?
| Shi, Yijiang; Frost, Patrick J; Hoang, Bao Q et al. (2008) IL-6-induced stimulation of c-myc translation in multiple myeloma cells is mediated by myc internal ribosome entry site function and the RNA-binding protein, hnRNP A1. Cancer Res 68:10215-22 |
