Glioblastoma (GBM) is the most common malignant primary brain tumor of adults and one of the most lethal of all cancers. New therapeutic approaches are needed. Genomic, proteomic and mouse model studies implicate mTOR kinase as a compelling GBM target. The role of mTOR complex 1 in GBM is well recognized;the role of mTOR complex 2 is poorly understood. We present exciting preliminary data demonstrating a critical role for mTORC2 signaling in GBM in promoting therapeutic resistance to rapamycin and demonstrate that inhibition of both mTOR complexes is needed to potently induce GBM tumor cell death. This proposal brings together a highly experienced collaborative team with expertise in GBM signal transduction, mTORC2 biochemistry and GBM in vitro and in vivo models to illuminate the molecular circuitry of mTOR signaling in GBM and to develop and test a novel mTOR kinase inhibitor that inhibits both mTOR signaling complexes. We will apply novel mTOR biochemical assays to genetically defined GBM in vitro and in vivo models and meticulously characterized clinical samples to illuminate the molecular circuitry and functional importance of mTORC2 signaling in GBM. In partnership with Celgene, we will develop and test a novel mTOR kinase inhibitor with potent anti-mTORC1 and mTORC2 activity We will: 1) directly measure mTORC2 activity in genetically defined GBM models and clinical samples and identify upstream activators and downstream effectors of mTORC2;2) determine whether combined inhibition of both mTOR signaling complexes is required to block tumor growth and 3) determine the efficacy of the novel mTOR kinase inhibitor for treatment of GBM patients including identifying patients most likely to benefit from the drug.

Public Health Relevance

The proposed studies challenge current research and clinical practice assumptions about mTOR as a GBM target. They address a major gap in our understanding of mTOR signaling and create a pathway to translation through development and testing of a novel mTOR kinase inhibitor. We anticipate that the results obtained from this proposal will have significant impact on the treatment of GBM patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS073831-01A1
Application #
8187754
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fountain, Jane W
Project Start
2011-06-15
Project End
2016-05-31
Budget Start
2011-06-15
Budget End
2012-05-31
Support Year
1
Fiscal Year
2011
Total Cost
$346,734
Indirect Cost
Name
University of California Los Angeles
Department
Pathology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Turner, Kristen M; Deshpande, Viraj; Beyter, Doruk et al. (2017) Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity. Nature 543:122-125
Gu, Yuchao; Albuquerque, Claudio P; Braas, Daniel et al. (2017) mTORC2 Regulates Amino Acid Metabolism in Cancer by Phosphorylation of the Cystine-Glutamate Antiporter xCT. Mol Cell 67:128-138.e7
Villa, Genaro R; Hulce, Jonathan J; Zanca, Ciro et al. (2016) An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers. Cancer Cell 30:683-693
Masui, Kenta; Shibata, Noriyuki; Cavenee, Webster K et al. (2016) mTORC2 activity in brain cancer: Extracellular nutrients are required to maintain oncogenic signaling. Bioessays 38:839-44
Wei, Wei; Shin, Young Shik; Xue, Min et al. (2016) Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma. Cancer Cell 29:563-573
Masui, Kenta; Cavenee, Webster K; Mischel, Paul S (2016) Cancer metabolism as a central driving force of glioma pathogenesis. Brain Tumor Pathol 33:161-8
Tanaka, Kazuhiro; Sasayama, Takashi; Irino, Yasuhiro et al. (2015) Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment. J Clin Invest 125:1591-602
Masui, Kenta; Cavenee, Webster K; Mischel, Paul S (2015) mTORC2 and Metabolic Reprogramming in GBM: at the Interface of Genetics and Environment. Brain Pathol 25:755-9
Liu, Feng; Hon, Gary C; Villa, Genaro R et al. (2015) EGFR Mutation Promotes Glioblastoma through Epigenome and Transcription Factor Network Remodeling. Mol Cell 60:307-18
Masui, Kenta; Tanaka, Kazuhiro; Ikegami, Shiro et al. (2015) Glucose-dependent acetylation of Rictor promotes targeted cancer therapy resistance. Proc Natl Acad Sci U S A 112:9406-11

Showing the most recent 10 out of 35 publications