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 #
5R01NS073831-05
Application #
8675968
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fountain, Jane W
Project Start
2011-06-15
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
$345,736
Indirect Cost
$121,534
Name
Ludwig Institute for Cancer Research Ltd
Department
Type
DUNS #
627922248
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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