Efficacy of combining tumor treating fields (TTFields) with a PARP inhibitor in ovarian cell lines (300.5)

Abstract

Objectives: PARP inhibition demonstrates clinical effectiveness in patients with solid tumors and deleterious BRCA mutations. The use of PARP inhibitors is specifically relevant in ovarian cancer, as one of three women with this malignancy harbor BRCA mutations. Tumor Treating Fields (TTFields) are alternating electric fields with antimitotic effects on cancerous cells, which are approved to treat patients with glioblastoma and malignant pleural mesothelioma. TTFields were shown to induce a state of BRCAness in several cancerous cell lines. The objective of this study was to explore the potential of combining TTFields with PARP inhibition for the treatment of ovarian cancer based on in vitro work. Methods: Ovarian carcinoma cells, A2780 (BRCA1/2 wild type) and OVCAR3 (BRCA1 wild type, BRCA2 mutated), were treated for 72 h with TTFields (at an intensity of 1.2 V/cm RMS and frequency of 200 kHz) using the in vitro system. The effectiveness of TTFields in combination with the PARP inhibitor niraparib was examined by measuring cell counts, clonogenic potential, overall effect (multiplicity product of cytotoxicity and clonogenicity), and apoptosis induction. Results: The application of TTFields to A2780 or OVCAR3 cells resulted in about 50% reduction in cell counts. Niraparib displayed a dose-dependent cytotoxic effect on both cell lines. Co-application of niraparib and TTFields resulted in enhanced cytotoxicity compared to the effect of niraparib or TTFields alone. TTFields also elevated the effects of niraparib on the colony-forming ability of the cells, the overall effect, and apoptosis. Conclusions: These results suggest a potential benefit for concomitant treatment of TTFields with niraparib in ovarian cancer. Additional experiments will examine the effect on the BRCA-FANC pathway in ovarian cancer. Objectives: PARP inhibition demonstrates clinical effectiveness in patients with solid tumors and deleterious BRCA mutations. The use of PARP inhibitors is specifically relevant in ovarian cancer, as one of three women with this malignancy harbor BRCA mutations. Tumor Treating Fields (TTFields) are alternating electric fields with antimitotic effects on cancerous cells, which are approved to treat patients with glioblastoma and malignant pleural mesothelioma. TTFields were shown to induce a state of BRCAness in several cancerous cell lines. The objective of this study was to explore the potential of combining TTFields with PARP inhibition for the treatment of ovarian cancer based on in vitro work. Methods: Ovarian carcinoma cells, A2780 (BRCA1/2 wild type) and OVCAR3 (BRCA1 wild type, BRCA2 mutated), were treated for 72 h with TTFields (at an intensity of 1.2 V/cm RMS and frequency of 200 kHz) using the in vitro system. The effectiveness of TTFields in combination with the PARP inhibitor niraparib was examined by measuring cell counts, clonogenic potential, overall effect (multiplicity product of cytotoxicity and clonogenicity), and apoptosis induction. Results: The application of TTFields to A2780 or OVCAR3 cells resulted in about 50% reduction in cell counts. Niraparib displayed a dose-dependent cytotoxic effect on both cell lines. Co-application of niraparib and TTFields resulted in enhanced cytotoxicity compared to the effect of niraparib or TTFields alone. TTFields also elevated the effects of niraparib on the colony-forming ability of the cells, the overall effect, and apoptosis. Conclusions: These results suggest a potential benefit for concomitant treatment of TTFields with niraparib in ovarian cancer. Additional experiments will examine the effect on the BRCA-FANC pathway in ovarian cancer.