R. Frechtel-Gerzi1, D. Gerasimova1, E. Zeevi1, H. Mumblat1, Y. Eid Mutlak1, Y. Shmueli1, R. Monin1, H. Fishman1, I. Schlachet-Drukerman1, N. Flint-Brodsly1, E. Dor-On1, I. Tzchori1, A. Haber1, M. Giladi1, U. Weinberg1, Y. Palti1, G. Palmer2, and A. Alvarez Secord3; 1Novocure Ltd, Haifa, Israel, 2Department of Radiation Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, NC, 3Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke Cancer Institute, Duke University Medical Center, Durham, NC
Purpose/Objective(s): Cervical cancer is a significant health concern. Patients with advanced, recurrent, or metastatic disease require systemic therapy. Cisplatin chemotherapy is typically the backbone of first-line therapy. TTFields are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression. TTFields have shown benefit when applied together with cisplatin in other tumor types. This preclinical study assessed the efficacy of TTFields concurrent with cisplatin for cervical cancer treatment. Materials/
Methods: Human cervical cancer cell lines (Ca Ski, HeLa, and SiHa cells) were exposed to TTFields (200 kHz, 72 h) together with varying cisplatin doses. Treated cells were then analyzed for cell count and colony formation. Overall effect was calculated from the percent reductions in cell count and colony formation. TTFields-treated cells were further evaluated for induction of DNA damage (using fluorescent detection of the marker ?H2AX) and for changes in expression of Fanconi Anemia (FA)-BRCA pathway proteins (via Western blotting). In vivo, mice were orthotopically inoculated with TC-1/Luc cervical cancer model cells and allowed to develop tumors for 8 days. Mice were then treated with continuous TTFields (200 kHz) or sham-heat for 11 days, and cisplatin (1 mg/kg) or vehicle IP injected on treatment days 1 and 6. At treatment end, tumors were examined with in vivo imaging system (IVIS) and weighed. Results: TTFields treatment augmented the effects of cisplatin on cervical cancer cells, as seen from the decrease in cell number and overall effect. TTFields induced downregulation of FA-BRCA pathway proteins, which are involved in repairing cisplatin-induced DNA damage, with consequent increase of DNA damage levels. In animals, TTFields treatment alongside cisplatin resulted in significantly lower tumor growth relative to control mice (by 36% or 17% for IVIS and tumor weight measurements, respectively; p-value < 0.05), to mice treated with cisplatin alone (by 51% or 31% for IVIS and tumor weight measurements, respectively; p-value < 0.05), and to mice treated with TTFields alone (by 51% for IVIS measurements, p-value < 0.05). Conclusion: TTFields enhance the effectiveness of cisplatin for treatment of cervical cancer, both in vitro and in vivo. The conditional vulnerability of the cells due to the TTFields-induced BRCAness state may account for this enhanced efficacy. The preclinical results suggest that TTFields should be further explored as a potential treatment for cervical cancer.
