Multiple myeloma is a plasma cell tumor that resides in the bone marrow and utilizes interleukin-6 (IL-6) as a specific tumor growth factor. The signal transduction pathways that mediate growth of IL-6-dependent and -independent myeloma clones are unknown. Our preliminary results indicate that the AKT kinase participates in tumor cell proliferation. AKT is phosphorylated in plasma cells of myeloma patients and is activated in myeloma cell lines, either constitutively, or by exposure to IL-6. Furthermore, inhibition of AKT activation and activity prevents myeloma cell proliferation in vitro. Our results also support the hypothesis that AKT promotes myeloma cell growth via downstream signaling that is dependent upon the mammalian target of rapamycin (mTOR) and mTOR's ability to induce phosphorylation of the p70S6kinase, 4E-BP1 translational repressor and STAT3. Rapamycin and its recently developed analogue, CCI-779, are potent inhibitors of mTOR, and CCI-779 has entered clinical trials. Thus, the broad objective of this proposal is to provide scientific support for use of CCI-779 to inhibit mTOR in myeloma patients. A secondary long range goal is to examine characteristics of patients' tumor cells that would identify sensitivity to this drug. To accomplish these goals, our specific aims include: ? ? I. To identify the molecular mechanism of AKT activation in myeloma ? ? II. To determine if p70, 4E-BP1 and STAT3 are important AKT targets in myeloma cells ? ? III. To demonstrate that inhibition of phosphorylation of p70 and/or 4E-BP1 and STAT3 inhibits myeloma cell growth ? ? IV. To investigate the use of CCI-779 for treatment of myeloma in a murine model. ? ? Our general experimental plan is to test our hypotheses in myeloma cell lines where we have an unlimited number of cells and then test the generality and significance of the results in freshly obtained myeloma plasma cells from patients.
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