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

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA111448-05
Application #
7591111
Study Section
Special Emphasis Panel (ZRG1-ONC-Q (01))
Program Officer
Forry, Suzanne L
Project Start
2005-06-01
Project End
2011-04-30
Budget Start
2009-05-01
Budget End
2011-04-30
Support Year
5
Fiscal Year
2009
Total Cost
$188,765
Indirect Cost
Name
Brentwood Biomedical Research Institute
Department
Type
DUNS #
197170756
City
Los Angeles
State
CA
Country
United States
Zip Code
90073
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Hoang, Bao; Shi, Yijiang; Frost, Patrick J et al. (2016) SGK Kinase Activity in Multiple Myeloma Cells Protects against ER Stress Apoptosis via a SEK-Dependent Mechanism. Mol Cancer Res 14:397-407
Shi, Y; Yang, Y; Hoang, B et al. (2016) Therapeutic potential of targeting IRES-dependent c-myc translation in multiple myeloma cells during ER stress. Oncogene 35:1015-24
Shi, Yijiang; Daniels-Wells, Tracy R; Frost, Patrick et al. (2016) Cytotoxic Properties of a DEPTOR-mTOR Inhibitor in Multiple Myeloma Cells. Cancer Res 76:5822-5831
Yoo, Esther M; Trinh, Kham R; Tran, Danh et al. (2015) Anti-CD138-targeted interferon is a potent therapeutic against multiple myeloma. J Interferon Cytokine Res 35:281-91
Shi, Yijiang; Frost, Patrick; Hoang, Bao et al. (2014) MNK1-induced eIF-4E phosphorylation in myeloma cells: a pathway mediating IL-6-induced expansion and expression of genes involved in metabolic and proteotoxic responses. PLoS One 9:e94011
Bardeleben, Carolyne; Sharma, Sanjai; Reeve, Joseph R et al. (2013) Metabolomics identifies pyrimidine starvation as the mechanism of 5-aminoimidazole-4-carboxamide-1-?-riboside-induced apoptosis in multiple myeloma cells. Mol Cancer Ther 12:1310-21
Frost, Patrick; Berlanger, Eileen; Mysore, Veena et al. (2013) Mammalian target of rapamycin inhibitors induce tumor cell apoptosis in vivo primarily by inhibiting VEGF expression and angiogenesis. J Oncol 2013:897025
Shi, Y; Frost, P; Hoang, B et al. (2013) MNK kinases facilitate c-myc IRES activity in rapamycin-treated multiple myeloma cells. Oncogene 32:190-7
VanderWall, Kristina; Daniels-Wells, Tracy R; Penichet, Manuel et al. (2013) Iron in multiple myeloma. Crit Rev Oncog 18:449-61

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