Gliomas are the most common primary malignancy of the central nervous system and are typically rapidly proliferating tumors resistant to chemotherapeutic intervention. Their complex and heterogeneous nature has hampered progress towards the development of successful therapies. The mammalian target of rapamycin (mTOR) kinase has emerged as an attractive target for therapeutic intervention in gliomas. Two multisubunit complexes containing mTOR exist, mTORC1 and mTORC2 which differ in their regulatory subunit compositions containing Raptor and Rictor, respectively. While hyperactive mTORC1 activity has been targeted in many cancers, including glioma with limited success, dysregulated mTORC2 function has only recently begun to be investigated. In this application we propose to 1). dissect the mechanism(s) of Rictor overexpression in gliomas, 2). clarify a recently identified genetic modifier of Rictor-mediated gliomagenesis potentially linking the mTORC2 and Hippo tumor suppressor signaling pathways and 3.) evaluate a novel mTORC2 specific small molecule inhibitor in genetically engineered mouse (GEM) models of the disease. We also propose to investigate and chemically modify the inhibitor to build in additional activitie against both the mTORC2 kinase and drug resistant gliomas.

Public Health Relevance

Successful completion of this project will substantiate a preclinical rationale for the continued development of mTORC2 specific inhibitors for trials in patients with glioma. Additionally, this study will provide information as to the operative mechanism(s) contributing to gliomagenesis as a result of aberrant mTORC2 activities.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Spalholz, Barbara A
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Brentwood Biomedical Research Institute
Los Angeles
United States
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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, 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
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
Holmes, Brent; Lee, Jihye; Landon, Kenna A et al. (2016) Mechanistic Target of Rapamycin (mTOR) Inhibition Synergizes with Reduced Internal Ribosome Entry Site (IRES)-mediated Translation of Cyclin D1 and c-MYC mRNAs to Treat Glioblastoma. J Biol Chem 291:14146-59
Artinian, Nicholas; Cloninger, Cheri; Holmes, Brent et al. (2015) Phosphorylation of the Hippo Pathway Component AMOTL2 by the mTORC2 Kinase Promotes YAP Signaling, Resulting in Enhanced Glioblastoma Growth and Invasiveness. J Biol Chem 290:19387-401
Benavides-Serrato, Angelica; Anderson, Lauren; Holmes, Brent et al. (2014) mTORC2 modulates feedback regulation of p38 MAPK activity via DUSP10/MKP5 to confer differential responses to PP242 in glioblastoma. Genes Cancer 5:393-406
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
Yang, Yonghui; Bardeleben, Carolyne; Frost, Patrick et al. (2014) DEPTOR is linked to a TORC1-p21 survival proliferation pathway in multiple myeloma cells. Genes Cancer 5:407-19
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
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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