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Interferon type I-based immunotherapy targeting glioma stem cells

English title Interferon type I-based immunotherapy targeting glioma stem cells
Applicant Weller Michael
Number 166634
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 01.07.2016 - 30.06.2019
Approved amount 499'693.00
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Keywords (4)

glioma; glioma stem cells; therapy; interferon beta

Lay Summary (German)

Lead
Glioblastome sind die häufigsten bösartigen Hirntumoren. Die mittlere Überlebenszeit beträgt trotz intensiver Therapie kaum mehr als 12 Monate da sich Glioblastome mit den herkömmlichen Methoden der Strahlen- und Chemotherapie nur unzureichend abtöten lassen. Präklinische Studien haben gezeigt, dass eine Subpopulation von Tumorzellen, die Glioblastom-Stammzellen, vermutlich für die Resistenz gegenüber der Standardtherapie verantwortlich sind. Ein vielversprechender neuer Therapieansatz zur zielgerichteten Bekämpfung dieser Zellpopulation soll in diesem Projekt untersucht werden.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Experimentelle Studien unseres Labors haben gezeigt, dass Glioblastom-Stammzellen durch Interferone bekämpft werden können. Interferone sind körpereigene Eiweisse, die u.a. bei der Abwehr von Viruserkrankungen eine wichtige Rolle spielen. Wir haben herausgefunden, dass die Zellen durch die Behandlung mit Interferon gegenüber  der Standardtherapie sensibilisiert und spezifische negative Eigenschaften dieser Zellen gehemmt werden. Ausserdem konnte das Überleben von tumortragenden Mäusen, die mit Interferon behandelt wurden, deutlich verlängert werden. In Untersuchungen zu Veränderungen der Genexpression von Interferon-behandelten Glioblastom-Stammzellen wurden Kandidatengene identifiziert, die die therapeutischen Effekte von Interferonen vermitteln könnten. Darunter befinden sich zahlreiche immunrelevante Gene. Deshalb werden wir Mausmodelle etablieren, die es erlauben, nicht nur den Effekt auf Tumorzellen, sondern auch die Reaktion des Körpers zu untersuchen.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Die vielversprechenden Forschungsergebnisse sollten möglichst schnell in der Klinik Anwendung finden, da Interferon zur Behandlung der Multiplen Sklerose eingesetzt wird und daher umfangreiche Kenntnisse über die Verträglichkeit dieser Therapie existieren.
Direct link to Lay Summary Last update: 30.03.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Profound, durable and MGMT‐independent sensitivity of glioblastoma cells to cyclin‐dependent kinase inhibition
Le Rhun Emilie, Achenbach Caroline, Lohmann Birthe, Silginer Manuela, Schneider Hannah, Meetze Kristan, Szabo Emese, Weller Michael (2019), Profound, durable and MGMT‐independent sensitivity of glioblastoma cells to cyclin‐dependent kinase inhibition, in International Journal of Cancer, 145(1), 242-253.
Age-associated and therapy-induced alterations in the cellular microenvironment of experimental gliomas
Schneider Hannah, Lohmann Birthe, Wirsching Hans-Georg, Hasenbach Kathy, Rushing Elisabeth J., Frei Karl, Pruschy Martin, Tabatabai Ghazaleh, Weller Michael (2017), Age-associated and therapy-induced alterations in the cellular microenvironment of experimental gliomas, in Oncotarget, 8(50), 87124-87135.
Autocrine activation of the IFN signaling pathway may promote immune escape in glioblastoma
Silginer Manuela, Nagy Sara, Happold Caroline, Schneider Hannah, Weller Michael, Roth Patrick (2017), Autocrine activation of the IFN signaling pathway may promote immune escape in glioblastoma, in Neuro-Oncology, 19(10), 1338-1349.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Holger Moch, Institute of Pathology, University Hospital Zurich Switzerland (Europe)
- Research Infrastructure
Prof. Dr. Luca Regli, Department of Neurosurgery, University Hospital Zurich Switzerland (Europe)
- Research Infrastructure
Dr. D. Baker, Biogen, Boston, MA United States of America (North America)
- Industry/business/other use-inspired collaboration
Prof. Dr. Guido Reifenberger, Institute of Neuropathology, University of Dusseldorf Germany (Europe)
- Research Infrastructure
Prof. Dr. Martin Pruschy, Department of Radiation Oncology, University Hospital Zurich Switzerland (Europe)
- Research Infrastructure
Prof. Dr. Matthias Guckenberger, Department of Radiation Oncology, University Hospital Zurich Switzerland (Europe)
- Research Infrastructure
Prof. Dr. Elisabeth Rushing, Institute of Pathology Switzerland (Europe)
- Research Infrastructure

Associated projects

Number Title Start Funding scheme
185155 The role of interferon type I signalling in the malignant phenotype and response to immune checkpoint inhibition in glioblastoma 01.07.2019 Project funding (Div. I-III)
146213 Interferon-ß-basierte Strategien zur Ueberwindung der Therapieresistenz des Glioblastoms unter besonderer Berücksichtigung von Tumorstammzellen 01.07.2013 Project funding (Div. I-III)
185155 The role of interferon type I signalling in the malignant phenotype and response to immune checkpoint inhibition in glioblastoma 01.07.2019 Project funding (Div. I-III)
146213 Interferon-ß-basierte Strategien zur Ueberwindung der Therapieresistenz des Glioblastoms unter besonderer Berücksichtigung von Tumorstammzellen 01.07.2013 Project funding (Div. I-III)
147651 Focused Ultrasound-Mediated Delivery of Encapsulated MGMT Antagonists for the Treatment of Temozolomide-Resistant Glioblastoma 01.03.2014 Sinergia
177080 MIG-ART - MRI gestützte adaptive Radio-Onkologie 01.06.2018 R'EQUIP
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)

Abstract

The median survival of patients with glioblastoma, the most malignant subtype of glioma, is still limited to approximately one year, despite multi-modal therapy, in population-based studies. The introduction of the alkylating agent temozolomide (TMZ) has improved the outcome selectively in glioblastoma patients with tumors exhibiting promoter methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene, but even these patients eventually all die from their disease. Anti-angiogenic agents such as bevacizumab or cilengitide did not prolong survival in phase III clinical trials reported in 2014. A population of tumor cells 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 current clinical approaches of radiotherapy (RT), classical cytotoxic chemotherapy, and anti-angiogenesis.We have characterized (i) a type I (alpha/beta) interferon-dependent pathway of sensitization of GIC cultures to TMZ and RT, (ii) a specific inhibitory activity of IFN-beta against sphere formation capacity, a hallmark of stemness in GIC cultures, and (iii) a profound survival prolongation of nude mice carrying orthotopic LN-229 human glioma xenografts in response to systemic pegylated IFN-beta treatment. We have performed transcriptomic and proteomic profiling of IFN-beta-treated GIC in vitro to identify candidate genes mediating these biological responses. Since several immune relevant genes were identified in these analyses, too, we propose to establish syngeneic mouse glioma models to study efficacy, safety and tolerability of GIC-targeted IFN-beta therapy, including analyses not only of intrinsic glioma cell responses, but also of altered immune cell responses and microenvironmental changes. Since IFN-beta is widely used for the treatment of human patients with multiple sclerosis, there is considerable knowledge on its safety in patients with brain disease, allowing for rapid translation of novel IFN-beta-based strategies into the clinic.
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