Gliomas account for about 60% of all primary CNS tumors. Glioblastoma (GBM) or grade IV gliomas which comprise 50.9% of all gliomas are the most malignant form. Glioblastoma tumors are highly heterogeneous and there is a complex interaction among different types of tumor cells and stromal cells within the tumor. Recently it has been shown that the majority of tumor cells do not have the capacity to recapitulate a phenocopy of the original tumor and that only a small subpopulation of cells in the tumor, called cancer stem cells, have that ability upon xenotransplantation in nude mice. These cancer stem cells appear to be more resistant to conventional therapy, like chemotherapy and radiation, as compared to the non-cancer stem cells. Following current therapy for high-grade glioma tumors, most patients die within a year from a new secondary tumor foci forming within one centimeter of the resected area. These foci are enriched for cancer stem cells, and it is likely that they are responsible for tumor recurrence. Our proposal focuses on identifying small molecule drugs which can increase therapeutic efficacy for GBM stem cells. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is regarded as a potential anti-cancer agent. However, a considerable number of different types of cancer cells, including GBM, are resistant to apoptosis induction by TRAIL. We plan to identity drug candidates which either kill primary GBM stem cells directly or can sensitize these cells to TRAIL-induced apoptosis. We will use a high throughput apoptosis-screening assay which we have developed based on the naturally secreted Gaussia luciferase and screen different small molecule libraries including ones containing FDA-approved drugs which crosses the blood-brain barrier. We will validate the most promising drug hits in our experimental glioma stem cells-bioluminescent model in vivo.

Public Health Relevance

The purpose of the work outlined in this proposal is to use the naturally secreted Gaussia luciferase as a reporter for high throughput screening in order to identify novel glioblastoma stem cells therapeutics. The drug candidates will be validated in dose- and time-dependent manner in culture as well as in our experimental glioblastoma stem cells-bioluminecence model in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS064983-04
Application #
8308009
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fountain, Jane W
Project Start
2009-09-30
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$379,444
Indirect Cost
$165,069
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Crommentuijn, Matheus H W; Maguire, Casey A; Niers, Johanna M et al. (2016) Intracranial AAV-sTRAIL combined with lanatoside C prolongs survival in an orthotopic xenograft mouse model of invasive glioblastoma. Mol Oncol 10:625-34
Kantar, Rami S; Lashgari, Ghazal; Tabet, Elie I et al. (2016) Imaging Tumor Vascularity and Response to Anti-Angiogenic Therapy Using Gaussia Luciferase. Sci Rep 6:26353
Crommentuijn, Matheus Hw; Kantar, Rami; Noske, David P et al. (2016) Systemically administered AAV9-sTRAIL combats invasive glioblastoma in a patient-derived orthotopic xenograft model. Mol Ther Oncolytics 3:16017
Degeling, M Hannah; Bovenberg, M Sarah S; Tannous, Marie et al. (2014) Gaussia luciferase-based mycoplasma detection assay in mammalian cell culture. Methods Mol Biol 1098:47-55
Teng, Jian; Hejazi, Seyedali; Badr, Christian E et al. (2014) Systemic anticancer neural stem cells in combination with a cardiac glycoside for glioblastoma therapy. Stem Cells 32:2021-32
Maguire, Casey A; Bovenberg, M Sarah; Crommentuijn, Matheus Hw et al. (2013) Triple bioluminescence imaging for in vivo monitoring of cellular processes. Mol Ther Nucleic Acids 2:e99
Bovenberg, M Sarah S; Degeling, M Hannah; Hejazi, Seyedali et al. (2013) Multiplex blood reporters for simultaneous monitoring of cellular processes. Anal Chem 85:10205-10
Badr, Christian E; Van Hoppe, Stephanie; Dumbuya, Hawasatu et al. (2013) Targeting cancer cells with the natural compound obtusaquinone. J Natl Cancer Inst 105:643-53
Degeling, M Hannah; Bovenberg, M Sarah S; Lewandrowski, Grant K et al. (2013) Directed molecular evolution reveals Gaussia luciferase variants with enhanced light output stability. Anal Chem 85:3006-12
Maguire, Casey A; Crommentuijn, Matheus Hw; Mu, Dakai et al. (2013) Mouse gender influences brain transduction by intravascularly administered AAV9. Mol Ther 21:1470-1

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