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Interferon-ß-basierte Strategien zur Ueberwindung der Therapieresistenz des Glioblastoms unter besonderer Berücksichtigung von Tumorstammzellen

English title Interferon-ß-based, cancer stem cell-targeted strategies to overcome the treatment resistance of glioblastomas
Applicant Weller Michael
Number 130122
Funding scheme Project funding (Div. I-III)
Research institution Neurologische Klinik Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Experimental Cancer Research
Start/End 01.07.2010 - 30.06.2013
Approved amount 468'000.00
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Keywords (5)

glioma; stem cell; interferon beta; chemoresistance;

Lay Summary (English)

Lead
Lay summary
Gliomas are intrinsic tumors of the brain. Glioblastoma is the most common of these brain tumors and characterized by a poor prognosis. It can occur in all age groups, is more common in the elderly, and affects 3 of 100,000 individuals per year. Half of the patients die within 7 months of diagnosis. The resistance of glioblastomas to conventional therapy is based on their infiltrating growth pattern which precludes a complete surgical removal and the limited efficacy of other treatment strategies such as radiotherapy or chemotherapy. However, the addition of temozolomide, an alkylating agent, to the standard therapy has improved the prognosis of glioblastoma patients. Based on promising preliminary findings in our laboratory, this project aims at investigating the effects of interferon (IFN)-beta in combination with temozolomide on glioma cells. These experiments include stem-like glioma cells that possess stem cell properties and may contribute to the resistance of gliomas to current therapeutic approaches. We will characterize the underlying mechanisms mediating synergy at the level of different cellular pathways using multiple in vitro and in vivo models. In summary, the experiments described in this research proposal shall lay the foundation for a novel, more effective treatment for human patients afflicted by glioblastoma.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Interferon-β Modulates the Innate Immune Response against Glioblastoma Initiating Cells.
Wolpert Fabian (2015), Interferon-β Modulates the Innate Immune Response against Glioblastoma Initiating Cells., in PLoS One, 10(10), e0139603.
Interferon-β induces loss of spherogenicity and overcomes therapy resistance of glioblastoma stem cells.
Happold Caroline (2014), Interferon-β induces loss of spherogenicity and overcomes therapy resistance of glioblastoma stem cells., in Molecular Cancer Therapeutics, 13(4), 948-961.

Collaboration

Group / person Country
Types of collaboration
Universität Düsseldorf Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Universität Regensburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Society for Neuro-Oncology Meeting 2011 Poster IFN-beta 17.11.2011 Orange County, California, United States of America Weller Michael;
EANO meeting 2010 Poster IFN-beta 16.09.2010 Maastricht, Netherlands Weller Michael;


Communication with the public

Communication Title Media Place Year
New media (web, blogs, podcasts, news feeds etc.) Internet-Präsenz Forschungsaktivitäten German-speaking Switzerland 2012

Associated projects

Number Title Start Funding scheme
146213 Interferon-ß-basierte Strategien zur Ueberwindung der Therapieresistenz des Glioblastoms unter besonderer Berücksichtigung von Tumorstammzellen 01.07.2013 Project funding (Div. I-III)

Abstract

The median survival of patients with glioblastoma, the most malignant subtype of glioma, is still limited to approximately 7 months, despite multi-modal therapy, in population-based studies. The introduction of the alkylating agent temozolomide has improved the outcome for glioblastoma patients selectively in patients with tumors exhibiting promoter methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene, but even these patients eventually all succumb to their disease. A population of cells within the tumor with characteristic stem cell features ("stem-like glioma cells") has been identified and characterized for specific biological features not shared by the bulk tumor cells. The resistance of these cells to the current modes of therapy might explain the inevitable recurrence of gliomas and defines these cells as novel targets to overcome the resistance of glioblastomas to radio- and chemotherapy. Preliminary data indicate a sensitization of glioma cells to temozolomide by the immune modulatory agent, interferon (IFN)-ß in vitro. The underlying molecular mechanisms have remained unclear, but, importantly, sensitization is not restricted to glioma cells exhibiting MGMT promoter methylation and may even specifically target the glioma stem cell population. Since IFN-ß is widely used for the treatment of multiple sclerosis, there is considerable knowledge on its safety profile in patients with brain disease, allowing for a rapid application to glioma patients in the case of convincing preclinical data. Here, we will explore in depth the differential activity of IFN-ß on stem-like versus bulk glioma cells with a focus on synergy with radiotherapy or temozolomide. We will characterize the molecular pathways of the IFN-ß-mediated sensitization at the level of signal transduction, altered gene expression and changes in microRNA expression. We will further investigate the putative impact of IFN-ß in combination with radio- or chemotherapy in a clinically relevant syngeneic glioma mouse model and on human glioma stem cell xenografts to assess the biological activity of these combinations in vivo. These studies shall lay the foundation for a novel, IFN-ß-based, more effective treatment for human patients afflicted by glioblastoma.
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