/ASBTRACT The main objective of this project is to provide a rationale for future therapeutic targeting of the TORC2 multiprotein complex in patients with multiple myeloma.
The aims i nclude studying mTOR kinase inhibitors against myeloma cell lines and patient primary cell specimens in vitro and in murine models in vivo, identifying the key TORC2 substrates that are the critical targets for inhibition and testing the role of DEPTOR protein expression in regulating the sensitivity of myeloma cells to TORC2 inhibitors. The viability versus death of myeloma cells as well as their ability to adhere and migrate in vitro will be studied. The identification and development of novel compounds which prevent protein-protein interactions within the TORC2 complex will also be attempted.

Public Health Relevance

The goal of the project is to provide further experimental support for development of TORC2 inhibitors against multiple myeloma. If successful, this new category of agents would present a significant addition to the current armamentarium of drugs used for this incurable malignancy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA111448-07
Application #
8484360
Study Section
Special Emphasis Panel (ZRG1-BMCT-C (09))
Program Officer
Forry, Suzanne L
Project Start
2004-12-01
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
7
Fiscal Year
2013
Total Cost
$173,214
Indirect Cost
$32,390
Name
Brentwood Biomedical Research Institute
Department
Type
DUNS #
197170756
City
Los Angeles
State
CA
Country
United States
Zip Code
90073
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
VanderWall, Kristina; Daniels-Wells, Tracy R; Penichet, Manuel et al. (2013) Iron in multiple myeloma. Crit Rev Oncog 18:449-61
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
Shi, Yijiang; Frost, Patrick; Hoang, Bao et al. (2011) IL-6-induced enhancement of c-Myc translation in multiple myeloma cells: critical role of cytoplasmic localization of the rna-binding protein hnRNP A1. J Biol Chem 286:67-78
Martin, Jheralyn; Masri, Janine; Cloninger, Cheri et al. (2011) Phosphomimetic substitution of heterogeneous nuclear ribonucleoprotein A1 at serine 199 abolishes AKT-dependent internal ribosome entry site-transacting factor (ITAF) function via effects on strand annealing and results in mammalian target of rapamycin co J Biol Chem 286:16402-13
Sharma, Sanjai; Liao, Wei; Zhou, Xiaofeng et al. (2011) Exon 11 skipping of E-cadherin RNA downregulates its expression in head and neck cancer cells. Mol Cancer Ther 10:1751-9
Cloninger, Cheri; Bernath, Andrew; Bashir, Tariq et al. (2011) Inhibition of SAPK2/p38 enhances sensitivity to mTORC1 inhibition by blocking IRES-mediated translation initiation in glioblastoma. Mol Cancer Ther 10:2244-56
Hoang, Bao; Frost, Patrick; Shi, Yijiang et al. (2010) Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor. Blood 116:4560-8
Hoang, Bao; Benavides, Angelica; Shi, Yijiang et al. (2009) Effect of autophagy on multiple myeloma cell viability. Mol Cancer Ther 8:1974-84

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