Radiochemotherapy-sensitizing and immunomodulatory effects of electrotherapy in primary spheroid cultures of glioblastoma stem cells

• Applicants: Privatdozentin Dr. Franziska Eckert; Professor Dr. Stephan Michael Huber
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology ; Nuclear Medicine, Radiotherapy, Radiobiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 471094086

Glioblastoma multiforme is the most common primary brain tumor in adults. Despite trimodal therapy (surgical resection, fractionated radiochemotherapy with temozolomide and temozolomide maintenance therapy) the prognosis of glioblastoma patient is still very poor with a median overall survival of below 2 years. In addition to the trimodal standard therapy, an electrotherapy with 200 kHz alternating fields (EF; TTFields, TumorTreatingFields, Novocure, Haifa, Israel) applied to the scalp via ceramic transducer arrays has been approved in Germany for glioblastoma in the primary and recurrent situation. EF concomitant to temozolomide maintenance therapy as compared to temozolomide maintenance therapy alone has been shown in a randomized prospective clinical trial to prolong the progression-free and overall survival of newly diagnosed glioblastoma patients who were treated with the standard protocol. The cellular mechanisms of the EF effects are largely unknown. Technically, it is possible to apply EF therapy to glioblastoma patients concomitantly to fractionated chemotherapy. Therefore, this project intends to quantify in vitro EF effects on radiation and temozolomide resistance, matrix infiltration, radio-immunological properties. Methodically, we are using primary spheroid cultures that enrich glioblastoma stem cells. The mesenchymal-to-proneural molecular signatures of these spheroid cultures associate with recurrence pattern and overall survival of our Tübingen cohort of glioblastoma patients. Therefore, we conclude that our cultures represent those glioblastoma cell populations relevant for the therapy response of the patients. Moreover, EF alternating fields will be applied by EF generators and application systems developed by ourselves which are superior to the Inovitro cell culture application system of Novocure in regard to data interpretability. Finally, by comparison of EF-sensitive with EF-resistant glioblastoma spheroid cultures, we plan to identify sensitivity markers and EF resistance mechanisms that may be used in the future for therapy stratification and overcoming of resistance in a personalized treatment approach.

• DFG Programme: Research Grants