gms | German Medical Science

Objective: Tumor Treating Fields (TTFields) have shown to be effective in the treatment of primary glioblastoma. However, the two-year survival rate is still below 50%. A promising approach to enhance the efficiency of TTFields is the use of drugs which extend metaphase-anaphase transition and telophase. In a previous study we tested the efficacy of the combined treatment of TTFields and the Aurora B kinase inhibitor AZD1152 in different established glioma cell lines: U87-MG, U87-MGshP53 and U-251. We found that the combined treatment of TTFields and AZD1152 led to a significant reduction in the number of glioma cells in all three cell lines as compared to each treatment alone.

Methods: In the present study we analyzed primary tumor-cell-lines to validate these data. In addition, we tested MLN8237, an Aurora A kinase inhibitor, to confirm that Aurora kinase inhibition is a valuable target for a combination therapy with TTFields. Primary tumor-cell lines were established from glioblastoma tissue taken intraoperatively. TTFields (1.6 V/cm RMS, 200 kHz) were applied for 72 hours using the inovitro system. AZD1152 was added to the media in concentrations of up to 100 nmol/l. Cell counts, cell cycle and clonogenic potential were determined at the end of treatment. Formation of multinuclear cells was determined using microscopic images of cells stained with crystal violet. MLN8237 was used in concentrations up to 50 nmol/l.

Results: The combined treatment of TTFields and AZD1152 led to a significant reduction in the number of primary glioblastoma cells (Mann-Whitney-U-test, p<0.001) as compared to each treatment alone. Microscopy images of glioblastoma cells stained with crystal violet after treatment, revealed high prevalence of multi nuclear cells in cells exposed to TTFields and AZD1152 (25nM) as compared to cells treated with AZD1152 (25nM) alone. Cells treated with TTFields and higher doses of AZD1152 (50–100nM) demonstrated increased rates of pyknosis. The combined treatment of MLN8237 and TTFields also resulted in a significant decrease of U87 MG cell numbers compared to each treatment alone (Mann-Whitney-U-test, p<0.01).

Conclusion: The results presented in this work demonstrate that the combination of TTFields and aurora kinase inhibition can be an effective treatment against glioma cells. Based on the above, there is a strong rational to continue exploring the potential of combining TTFields and aurora kinase inhibition in early clinical trials.