Thesis supervisors: Jana Jaal University of Tartu and Toomas Asser University of Tartu.
Opponent Daniel Zips, MD, Dr med, (University os Tübingen)
Glioblastoma multiforme (GBM) is the most aggressive malignant tumor of the brain being also extremely treatment-resistant. Postoperative radiotherapy and medicamentose treatment enables to achieve only short-term stability for few months only. The average life expectancy with GBM is approximately 12-15 months.
The aim of this study was to find opportunities to increase efficacy in the treatment of GBM. For this purpose tumor tissue samples removed during the operations were examined to identify several treatment resistant factors. It was demonstrated that treatment response and therefore life expectancy is dependent from tumor tissue DNA-reparation enzyme DNA-PK levels. DNA-PK enzyme is responsible for the reparation of the damage occurring from the antitumor treatment (such as DNA double helix) wherefore usual antitumor treatment may not give the expected results. The research concluded that the higher tumor DNA-PK level resulted in shorter life expectancy. One of the main reasons for the treatment failure is considered the stem cell resistance to radiotherapy shown by preclinical researches that this work’s clinical data did not support. Patients, whose tumor contained more CD133 stem cells pre-therapeutically, had better treatment response and longer life expectancy.
The research also demonstrated that postoperative treatment efficacy and life expectancy depends from the amount of tumor infiltrative inflammatory as well as immunity cells. GMF patients whose tumor tissue contained more CD63 inflammatory and immunity cells pre-radiotherapeutically had better treatment response.
In addition, it occurred that new medications widely tested in GBM treatment, such as angiogenesis inhibitors main target, vascular endothelial growth factor receptor 2 (VEGFR2) expression depends from the coverage of the inflammation in the tumor tissue. Therefore VEGFR2 expression dependency form the tumors microenvironment could be one of the reasons for the angiogenesis inhibitors non-effective treatment result.
In conclusion, for the better treatment results of GBM there are many opportunities and for more efficient antitumor treatment response it is effective not only to influence the tumor cells but also the stem cells of the tumor as well as the microenvironment of the tumor.