Funding tool: Basic research projects
Project-ID: LS12-006
Project start: 01. Oktober 2013
Project end: will follow
Runtime: 36 months / finished
Funding amount: € 250.000,00

Brief summary:

Aim of this project is to study the role of therapy resistance in glioblastoma. This will be achieved by close cooperation between the department of neurology at the LK St. Pölten-Lilienfeld and the Molecular Imaging group at the AIT Austrian Institute of Technology. Glioblastoma is the most occurring brain tumor in adults. Treatment strategies usually include surgery, chemo and/or radiation therapy. The standard treatment of glioblastoma multiforme includes surgical resection and concurred chemotherapy. Unfortunately the removal of the primary tumor mass only slows down the progression of the disease due to the infiltrative nature of glioma tumor cells into healthy brain tissue. Recent studies have shown, that failure in chemotherapy of glioma is related to ineffective delivery of chemotherapeutics to the invasive and infiltrative cells. This could be related to an overexpression of transporter proteins situated at the blood-brain barrier, which prevent therapeutic substances like tyrosin kinase inhibitors of reaching their effective concentration in the remaining tumor cells. Exactly this research question will be investigated in the project. We will generate P-glycoprotein overexpressing tumor cell based on the U87MG human glioma cell line. These two cell lines will be used for the generation of an orthotropic glioma model. The radiolabelled tyrosin kinase inhibitor (gefitinib) will then be investigated using PET-MRI. This will be done before and after administration of different doses of the multidrug transporter protein inhibitor (elacridar). From the in vivo PET data pharmacokinetic modeling will be performed, to identify the parameters which display the strongest correlation with transporter protein inhibition. In parallel, we will determine P-glycoprotein and breast cancer resistance protein expression in human glioma tumor samples. This will allow us to assess the transferability of the obtained data to the clinical setting.

Keywords:
glioblastoma, drug resistance, p-glycoprotein, positron emission tomography, magnetic resonance imaging