P11.19 Glioblastoma cancer stem cells proliferation and cell cycle arrest under TTFields influence

Abstract

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive and fastest growing-type among brain tumours. The current standard of care is a combination of surgery, radio- and chemotherapy. However, GBM is characterized by a poor prognosis and an average life expectancy of 15 months under current treatment. Tumor treating fields (TTFields) are low-intensity electric fields alternating at an intermediate frequency (200kHz), which have been demonstrated to block cell division and interfere with organelle assembly. It has been evaluated in randomized phase 3 trials in GBM and demonstrated to prolong progression-free survival and overall survival when administered together with standard maintenance temozolomide (TMZ) chemotherapy in patients. This technology represents the biggest step forward against GBM in more than a decade. METHODS Primary cultures of human glioblastoma enriched in cancer stem cells (GSCs) were stimulated using the InovitroTM System (NOVOCURE) for 72 hours. Remaining cells were collected for further experiments. RESULTS Our investigation has targeted GSCs, a subset of cells that are considered responsible for tumour recurrence and confer resistance to chemotherapy and radiotherapy. Our data show that after 72 hours of TTFields exposure, more than 60% of the cellular population are dead. The residual GSCs were able to recover proliferation as soon as TTFields application had ended. We used different combinations of TTFields exposure times and pharmacological treatments with the main objective to impair cell proliferation relapse. Prolong TTF stimulation kills more cells but survivor cells are still able to resume proliferation. The addition of 10 mM TMX increase drastically the efficacy of the TTFields treatment even if the few cells left were able to slowly form colonies in a single cell cloning assay. CONCLUSION GCSs are sensitive to TTFields and to the combining pharmacological treatment with TMZ. The strategy to optimize the antiproliferative action on GCSs relapse will be to find a best combination of anticancer drugs concentration, together with TTFields exposure.