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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA168700-03
Application #
8658059
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Spalholz, Barbara A
Project Start
2012-07-17
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brentwood Biomedical Research Institute
Department
Type
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90073
Benavides-Serrato, Angelica; Lee, Jihye; Holmes, Brent et al. (2017) Specific blockade of Rictor-mTOR association inhibits mTORC2 activity and is cytotoxic in glioblastoma. PLoS One 12:e0176599
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
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
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
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
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

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