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Tumor Treating Fields (TTFields) are a novel, noninvasive FDA-approved treatment modality for glioblastoma (GBM) that utilizes alternating electric fields. While the mechanism of action was at first exclusively attributed to the effects of TTFields on cells during mitosis, additional effects during interphase have recently come to light. The aim of our research is to elucidate the effect of TTFields on the cell cycle to advance the understanding of TTFields and to find novel targets for increasing its efficacy. We studied the effect of TTFields on cell cycle distribution by (propidium iodide and phospho-Histone H3 labeling) flow cytometry using double-thymidine block (DTB) synchronized cell populations. Following the release of the DTB, TTFields treatment caused GBM cells to accumulate in G2, which was prevented by concomitant exposure to a Wee1 inhibitor. Next, we compared the efficacy of TTFields with or without Wee1 or Chk1 inhibitors in multiple GBM cell lines (A172, SNB-19, and U251) by colony formation assays and observed a strong and synergistic decrease in colony formation potential in all cell lines. To investigate the underlying mechanism of G2 arrest, we quantified the amount of DNA damage, but found no difference in either γH2AX foci or comet tail moments between control and TTFields treated cells. To follow up on this surprising observation, we are using live cell imaging (inovitro Live™) of PIP-FUCCI-transduced cells. This tool will allow us to track individual cells, to evaluate the time spent in each phase of the cell cycle and to determine the ultimate cell fate in control and treatment conditions. Our finding that Wee1 or Chk1 inhibition dramatically boosts the efficacy of TTFields may have great implications for treatment of patients with TTFields. The in vivo validation of our in vitro findings will be performed in tumor-bearing mice by using the inovivo™ system.

neuro-oncology

EXTH-31. INCREASING TUMOR TREATING FIELDS (TTFIELDS) EFFICACY BY TARGETING THE G2 CELL CYCLE CHECKPOINT WITH WEE1 OR CHK1 INHIBITORS IN GLIOBLASTOMA CELL LINES