Sensitivity Multiple Myeloma Cells to mTOR Inhibitors

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DESCRIPTION (provided by applicant): The long term objective of this proposal is to improve medical management of patients with multiple myeloma. Our prior studies demonstrated that targeting the mammalian target of rapamycin (mTOR) with rapamycin or CCI-779 has great therapeutic potential in this malignancy and that the level of AKT activity determines sensitivity to mTOR inhibitors: When AKT activity is heightened, myeloma cells are hypersensitive to G1 arrest, while lowered AKT activity induces relative resistance. Inhibition of mTOR often inhibits cap-dependent translation and expression of critical cell cycle proteins. Consistent with this notion is the fact that mTOR inhibitors induced inhibition of cyclin-D and c-myc translation in sensitive myeloma cells while translation was unaffected in resistant cells. These findings have prompted the following hypothesis: Myeloma cells with high AKT activity are hypersensitive to the ability of mTOR inhibitors to depress D-cyclin and myc expression, thus explaining their sensitivity to G1 arrest. Furthermore, we hypothesize that AKT regulates this response by paralyzing the salvage pathway of cyclin/myc cap-independent translation and that this AKT-dependent function is mediated by function of internal ribosome entry sites (IRESes) in cyclin/myc RNA and the p38 MARK pathway. To test these hypotheses, our specific aims include: I. To test if the AKT-dependent regulation of sensitivity to mTOR inhibitors is explained by differential effects on expression of D-type cyclins and/or c-myc. II. To test if AKT's regulation of cyclin/myc expression is mediated by effects on translational efficiency. III. To identify alterations in IRES-associated trans-acting factors (ITAFs) that may explain AKTregulation of cap-independent translation. These studies will performed in myeloma cell lines as well as primary patient marrow specimens