Prof. Dr. med. Michael Weller

 

Main Goals, Keywords

• Development of novel approaches of immunotherapy for malignant brain tumors
• Definition of resistance mechanisms of glioblastoma stem cells to irradiation and chemotherapy
• Understanding and modulating angiogenesis in glioblastoma ·
  

Keywords: neurooncology, glioblastoma, immunotherapy, angiogenesis, cancer stem cells

Group Members

1 group leader, 2 MD scientists, 2 postdocs, 3 PhD students, 2 technicians

Previous, Current and Future Research

Development of novel approaches of immunotherapy for malignant brain tumors

Despite multimodal treatment, the prognosis for patients with malignant gliomas remains poor. Our immunotherapy projects aim at defining the basis for a novel immunotherapeutic approach targeting glioma-initiating cells with stem cell properties, commonly named glioma stem cells. These glioma stem cells are isolated from surgically removed tumor material and characterized for possible immunogenic properties with a focus on cell surface markers for immune recognition. The susceptibility of glioma stem cells towards an attack of immune effector cells in vitro and in vivo is examined, with the hope to develop novel approaches of tumor stem cell-specific vaccination against brain tumors. The Brain Tumor Center Zurich participates in the first phase III clinical trial of vaccination for glioblastoma patients with EGFRvIII-mutant tumors (ACT IV).

Definition of resistance mechanisms of cancer stem cells to irradiation and chemotherapy

There is emerging evidence that gliomas just like other tumors exhibit a hierarchic structure of cellular composition. Glioma stem cells are defined as less differentiated, multipotent and highly tumorigenic cells with self-renewal capacity. These cells form neurospheres under defined conditions and express markers of stem cells such as CD133 or nestin (see Figure). The glioma stem cells are thought to maintain tumor growth, and there is evidence that they might confer resistance to conventional radio- and chemotherapy. To explore this novel look at cancer resistance, glioma cells with and without stem cell properties will be compared regarding their resistance mechanisms to irradiation and currently used cancer chemotherapeutic agents.

Understanding and modulating angiogenesis in glioblastoma

The major focus of clinical research in Neuro-Oncology is currently on inhibiting angiogenesis using various pharmacological strategies. Here the Department of Neurology together with its clinical partner institutions in Zurich, within the Brain Tumor Center Zurich, is currently involved in various multicenter trials, e.g., by the European Organization for Research and Treatment of Cancer (EORTC) or initiated and led by Zurich, e.g., the ARTE trial on radiotherapy without or with bevacizumab for elderly patients with glioblastoma. In parallel, in a translational approach, using cell culture and animal models with innovative small animal imaging, we try to understand the signaling emanating from and to glioma cells in the context of angiogenesis and escape from anti-angiogenic strategies.

Techniques and Equipment

All standard methods of biochemistry, cell and molecular biology are used in our laboratory, e.g., real-time PCR, immunoblot, apoptosis and proliferation assays, cell cycle analysis, transfection techniques, siRNA technology, and immunological assays. We also use different in vivo rodent glioma models and in vivo glioma imaging in mice.

Major collaborators

Departments/Institutes of Neurosurgery, Neuroradiology, Neuropathology, Oncology, Radiation Oncology and Nuclear Medicine, University Hospital Zurich and University of Zurich USZ/UZH

Department of Neurooncology, Heidelberg, Germany

Institute for Biochemistry, Regensburg, Germany

Institute for Molecular Biology, Essen, Germany

Selected Publications

• Hasenbach K, Wiehr S, Herrmann C, Mannheim J, Cay F, Von Kürthy G, Bolmont T, Grathwohl SA, Weller M, Lengerke C, Pichler BJ, Tabatabai G. Monitoring the glioma tropism of bone marrow-derived progenitor cells by two-photon laser scanning microscopy and positron emission tomography. Neuro-Oncology 2012;14:471-481
  
• Happold C, Roth P, Wick W, Schmidt N, Florea AM, Silginer M, Reifenberger G, Weller M. Distinct molecular mechanisms of acquired resistance to temozolomide in glioblastoma cells. J Neurochem 2012122:444–455
  
• Roth P, Silginer M, Goodman SL, Hasenbach K, Thies S, Maurer G, Schraml P, Tabatabai G, Moch H, Tritschler I, Weller M. Integrin control of the transforming growth factor-b pathway in glioblastoma. Brain 2013;136:564-576