Abstract

/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.

  Funding Agency

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

  Institution

Name
Brentwood Biomedical Research Institute
Department
Type
DUNS #
197170756
City
Los Angeles
State
CA
Country
United States
Zip Code
90073

  Publications

Lee, Jihye; Shi, Yijiang; Vega, Mario et al. (2017) Structure-activity relationship study of small molecule inhibitors of the DEPTOR-mTOR interaction. Bioorg Med Chem Lett 27:4714-4724
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
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
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
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
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

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