Prof. Dr. med. Michael Weller

 

Main Goals, Keywords

• Development of novel approaches of immunotherapy for malignant brain tumors
• Definition of resistance mechanisms of cancer stem cells to irradiation and chemotherapy
• Initiation and conduct of clinical trials in Neuro-Oncology

Key words: neurooncology, malignant glioma, cell-based gene therapy, angiogenesis, adult hematopoietic stem cells, cancer stem cells

Group Members

1 group leader, 3 MD scientists, 1 PhD student, 2 technicians

Previous, Current and Future Research

Development of novel approaches of immunotherapy for malignant brain tumors gliomas

Despite multimodal treatment, the prognosis for patients with malignant gliomas remains poor. The 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 will be isolated from surgically removed tumor material and characterized for possible immunogenic properties with a focus on cell surface markers for immune recognition. Further, the antigen-processing machinery and cytokine secretion in the tumor stem cells will be compared with tumor cells without stem cell properties from the same patient. The susceptibility of glioma stem cells towards an attack of immune effector cells in vitro and in vivo will be examined, with the hope to develop novel approaches of tumor stem cell-specific vaccination against brain tumors.

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.

Initiation and conduct of clinical trials in Neuro-Oncology

The major progress in Neuro-Oncology in the last 20 years has been made through the conduction of prospective controlled clinical trials in the framework of large national and international cooperative efforts. The Department of Neurology together with its clinical partner institutions in Zurich is currently involved in various multicenter trials run by the European Organization for Research and Treatment of Cancer (EORTC) and has a leadership role in the registration trial for the novel integrin antagonist cilengitide (CENTRIC) in newly diagnosed glioblastoma. Novel projects include two randomized phase II trials: the DIRECTOR trial is conducted in Switzerland, Austria and Germany and will assess the efficacy of two different intensified dosing regimens of temozolomide for recurrent glioblastoma (NCT00941460); the ARTE trial will be conducted in 6 Swiss centers and will assess the combination of the antiangiogenic VEGF antibody, bevacizumab, with radiotherapy in elderly patients with glioblastoma.

Techniques and Equipment

Standard protocols in cell and molecular biology; lentiviral transduction; stereototactic intracerebral implantation of experimental gliomas; immunological methods; insertion of chronic cranial glass windows in mice, small animal imaging in collaboration with Prof. Dr. M. Rudin (Institute for Biomedical Engineering, ETHZ).

Major collaborators

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

Max Planck Institute for Biochemistry, Munich

German Glioma Network

Brain Tumor Network NGFN-PLUS

Selected Publications

• Weller, M., Stupp, R., Reifenberger, G., Brandes, A.A., Van den Bent, M.J., Wick, W., Hegi, M.E. MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nature Rev Neurol 6: 39-51 (2010).
  
• Weller, M., Felsberg, J., Hartmann, C., Berger, H., Steinbach, J.P., Schramm, J., Westphal, M., Schackert, G., Simon, M., Tonn, J.C., Heese, O., Krex, D., Nikkhah, G., Pietsch, T., Wiestler, O.D., Reifenberger, G., von Deimling, A., Loeffler, M., for the German Glioma Network. Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma. A prospective translational study of the German Glioma Network. J Clin Oncol 27: 5743-5750 (2009).
  
• Wick, W., Hartmann, C., Engel, C., Stoffels, M., Felsberg, J., Stockhammer, F., Sabel, M.C., Koeppen, S., Ketter, R., Meyermann, R., Rapp, M., Meisner, C., Kortmann, R., Pietsch, T., Wiestler, O.D., Ernemann, U., Bamberg, M., Reifenberger, G., von Deimling, A., Weller, M., for the Neurooncology Working Group (NOA) of the German Cancer Society. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. J Clin Oncol 27: 5874-5880 (2009).