PD Dr. Ghazaleh Tabatabai

 

Main Goals, Keywords

•    To design cell-based gene therapies against malignant gliomas
•    To study molecular mechanisms of resistance to antiangiogenic therapy
•    To identify the “barcode” of glioma-initiating cells

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

Group Members

1 group leader,1 postdoc, 1 MD scientist, 2 PhD students

Previous, Current and Future Research

•    To design cell-based gene therapies against malignant gliomas

Our long-term goal is to use autologous adult hematopoietic progenitor cells as cellular vehicles to deliver therapeutic molecules to malignant gliomas. We have characterized molecular mechanisms mediating the glioma tropism of adult hematopoietic progenitor cells (HPC) (Fig. 1). Our current focus is on optimizing imaging tools for tracking the glioma-mediated attraction of HPC in syngeneic mouse models using two-photon laser scanning microscopy (2P), magnetic resonance imaging (MRI) and positron emission tomography (PET). We plan to use ex vivo lentivirally transduced HPC for delivering therapeutic molecules to malignant gliomas in vivo.

Fig. 1: Experimental gliomas (blue cells) attract HPC (yellow cells) by a network of chemokines/receptor interactions. 

•    To study molecular mechanisms of resistance to antiangiogenic therapy

Angiogenesis inhibitors are currently applied within clinical trials for newly diagnosed and recurrent malignant gliomas. First data indicate that despite initial radiological responses the overall survival remains unsatisfactory due to aquired resistance to this treatment in malignant gliomas. To study molecular mechanisms mediating the resistance to antiangiogenic therapy, we have established the insertion of chronic cranial glass windows in mice to monitor angiogenesis in orthotopic experimental glimoas by 2P in vivo (Fig. 2). Our current focus is on characterizing changes in the vascular architecture during antiangiogenic therapies targeting proangiogenic factors in vivo. We plan to modify the expression of pro- or antiangiogenic factors and their receptors to identify key factors mediating the resistance to antiangiogenic therapy.

Fig. 2: Two-photon laser scanning microscopy. Red staining visualizes the blood vessels within the GFP-positive experimental glioma. 

•    To identify the “barcode” of glioma-initiating cells

Our longterm goal is to design therapies to target tumor-initiating cells in malignant gliomas. An important prerequisite is to characterize the “barcode” of these cells, i.e. the unique features that allow to distinguish them from the non-tumor-initiating cell population. Our current focus is to analyze cell surface markers and transcription factors in established glioma-initiating cell lines.

Techniques and Equipment

Standard protocols in cell and molecular biology. Lentiviral transduction. Adult hippocampal slice cultures. Stereototactic intracerebral implantation of experimental gliomas. Insertion of chronic cranial glass windows in mice. MRI & PET in collaboration with Prof. Dr. B. Pichler (Laboratory for Preclinical Imaging, Tübingen) and Prof. Dr. M. Rudin (Institute for Biomedical Engineering).

Selected Publications

• Tabatabai G, Hegi M, Stupp R, Weller M. Clinical implications of molecular neuropathology and biomarkers for malignant glioma. Curr Neurol Neurosci Rep. 2012 Jun;12(3):302-7. doi: 10.1007/s11910-012-0263-x. Review.
• 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 2-photon laser scanning microscopy and positron emission tomography. Neuro Oncol. 2012 Apr;14:471-81
• Schraivogel D, Weinmann L, Beier D, Tabatabai G, Eichner A, Zhu JY, Anton M, Sixt M, Weller M, Beier CP, Meister G. CAMTA1 is a novel tumour suppressor regulated by miR-9/9* in glioblastoma stem cells. EMBO J. 2011 Aug 19;30:4309-22
• Tabatabai G, Stupp R, van den Bent MJ, Hegi ME, Tonn JC, Wick W, Weller M. Molecular diagnostics of gliomas: the clinical perspective. Acta Neuropathol. 2010 Nov;120:585-92. Epub 2010 Sep 23. Review.

Funding

Swiss National Science Foundation, Wilhelm Sander-Stiftung, Oncosuisse

Current clinical projects

Study Coordinator of the phase II clinical trial “Dose-intensified rechallenge with temozolomide, one week on/one week off versus three weeks on/one week off in patients with progressive or recurrent glioblastoma (DIRECTOR)”, a multicenter randomized trial recruiting in 13 clinical centers in 3 countries (Switzerland, Austria, Germany) http://clinicaltrials.gov/ (Identifyer: NCT00941460)

Study Coordinator of the phase II clinical trial “Avastin plus radiotherapy in elderly patients with glioblastomas (ARTE)”, a multicenter randomized trial recruiting in Switzerland http://clinicaltrials.gov/ (Identifyer: NCT01443676)