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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 146213
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 01.07.2013 - 30.06.2016
Approved amount 493'920.00
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Keywords (4)

glioma; stem cell; chemoresistance; interferon beta

Lay Summary (German)

Lead
Charakterisierung des Effekts von Interferon-beta auf Glioblastomstammzellen
Lay summary
Glioblastome sind bösartige Tumoren, die aus Zellen des Gehirns entstehen. Obwohl in den letzten Jahren einige Fortschritte in der Behandlung erzielt wurden, bleibt die Prognose für die betroffenen Patienten weiterhin ausgesprochen schlecht. Selbst im Rahmen von klinischen Studien beträgt das mittlere Überleben nur etwa ein Jahr. Glioblastome kommen gehäuft bei älteren Menschen vor. Die Gründe hierfür sind nicht bekannt. Zunehmend besser verstanden sind die Mechanismen, die dazu führen, dass Gliomzellen gegenüber den verfügbaren Therapiemodalitäten resistent sind oder im Verlauf der Erkrankung eine Resistenz entwickeln. Neben der operativen Entfernung stehen die Bestrahlung und die Chemotherapie zur Verfügung. Interferon (IFN)-beta ist ein Zytokin, das im Körper vorkommt und auch therapeutisch eingesetzt werden kann. Wir haben festgestellt, dass Gliomzellen unter dem Einfluss von IFN-beta empfindlicher gegenüber Strahlen- und alkylierender Chemotherapie werden. Zudem bestehen teilweise deutliche Eigeneffekte von IFN-beta auf Gliomstammzellen, die innerhalb des Tumors eine besonders wichtige Rolle zu spielen scheinen. Da diese Tumorstammzellen möglicherweise auch zur Resistenz von Glioblastomen gegenüber den o.g. Therapieformen beitragen, müssen sie bei der Entwicklung neuer Therapieansätze in besonderer Form beachtet werden. Wir werden die Wirkung von IFN-beta auf Gliomstammzellen untersuchen und dabei Hochdurchsatzverfahren einsetzen, welche helfen werden, den Einfluss von IFN-beta detailliert zu charakterisieren. Ziel ist ein besseres Verständnis der durch IFN-beta vermittelten Effekte auf Gliomzellen, welches letztlich in neue und bessere Therapieansätze in der Behandlung von Glioblastom-Patienten einfliessen soll.
Direct link to Lay Summary Last update: 05.05.2013

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
Prof. Dr. Guido Reifenberger, Institute of Neuropathology, University of Dusseldorf Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Dr. Luca Regli, Department of Neurosurgery, University Hospital Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Deutscher Krebskongress 2016 Talk given at a conference Interferon-β modulates the innate immune response against glioblastoma initiating cells 24.02.2016 Berlin, Germany Weller Michael;


Associated projects

Number Title Start Funding scheme
130122 Interferon-ß-basierte Strategien zur Ueberwindung der Therapieresistenz des Glioblastoms unter besonderer Berücksichtigung von Tumorstammzellen 01.07.2010 Project funding (Div. I-III)
132847 Growth and differentiation factor (GDF)-15, microRNA and the immunophenotype of glioblastoma 01.02.2011 Project funding (Div. I-III)
132921 Human antibodies against misfolded proteins in neurodegenerative diseases 01.10.2010 Project funding (Div. I-III)
166634 Interferon type I-based immunotherapy targeting glioma stem cells 01.07.2016 Project funding (Div. I-III)
166634 Interferon type I-based immunotherapy targeting glioma stem cells 01.07.2016 Project funding (Div. I-III)
143991 Age-associated and therapy-induced alterations in the cellular microenvironment of experimental gliomas and their role for resistance to therapy 01.01.2013 Project funding (Div. I-III)
157763 MobiPET: A mobile, small animal PET scanner for molecular imaging 01.03.2015 R'EQUIP

Abstract

The median survival of patients with glioblastoma, the most malignant subtype of glioma, is still limited to less than one year, 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. Currently, mature data from two randomized trials exploring the anti-angiogenic agents, bevacizumab and cilengitide, are being awaited. A population of cells within the tumor with stem cell features, now commonly referred to as "glioma-initiating cells" (GIC), has been attributed a central role in the escape of glioblastomas from the current clinical approaches of radio- and chemotherapy.In the first funding period of this project, we have characterized an interferon (IFN)-ß-dependent pathway of sensitization of glioma, notably GIC, cultures to temozolomide and irradiation that was not mediated by down-regulation of MGMT expression and was independent of the TP53 mutational status. Moreover, we have characterized a specific inhibitory activity of IFN-ß against the sphere formation capacity, a hallmark of stemness in GIC cultures. Finally, we have observed that glioma cells produce type I interferons (alpha/beta) themselves, raising the possibility of autocrine signalling. In order to clarify the molecular pathways mediating the anti-GIC activity as well as the sensitization towards current modes of treatment, we have initiated high throughout studies at the levels of mRNA expression, miRNA expression, as well as proteomics. In the second funding period, the significance of candidate molecules and pathways identified using these screens shall be validated in vitro and, if confirmed, result in new treatment strategies that can be further explored in clinically relevant syngeneic mouse glioma as well as human GIC xenograft models in vivo. Since IFN-ß is widely used for the treatment of patients with multiple sclerosis, there is considerable knowledge on its safety profile in patients with brain disease, allowing for a rapid introduction of novel IFN-ß-based strategies into clinical exploration. Thus, we hope that this project will lay the foundation for the development of promising, more effective treatment options for patients afflicted by glioblastoma.
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