Abstract 3316: Tumor Treating Fields in combination with radiation cause significant delay in tumor growth in in-vivo mice modelsignificant delay in tumor growth in in-vivo mice model

Abstract

Abstract New physical cancer treatment modality called Tumor Treating Fields (TTFields) deliver low-intensity, intermediate frequency, alternating electric fields non-invasively to the tumor. TTFields is believed to inhibit mitosis as its primary mechanism of action. We previously showed that TTFields exposure decreased the expression of FANC/BRCA1 pathway genes, which play an essential role in DNA double strand break (DSB) repair. As a result, DNA DSB repair under IR exposure is downregulated, and most importantly, the TTFields alone increased gH2AX foci and chromatid aberrations as a function of TTFields time exposure. The length of newly replicated DNA decreased and R-loop formation increased after TTFields treatment, suggesting replication stress is induced by TTFields. Our research revealed that TTFields are involved in DNA damage and replication stress pathways besides mitosis, thus, we predicted that, by applying TTFields first, a conditional vulnerability environment would be created, rendering cells more susceptible to agents like radiation and chemotherapy. In accordance with our hypothesis, radiation susceptibility increased when cells were exposed to TTFields prior to IR treatment compared to IR treatment followed by TTFields. The combination of TTFields together with Radiation has been tested in-vivo with the newly designed Inovivo system. To measure tumor growth delay caused by TTFields treatment, three distinct syngenic tumor mouse models were utilized, namely LLC (Murine Lewis Lung Carcinoma), KPC63 (Pancreatic Cancer) and MC38 (Colon Cancer). Although TTField exposure decreased tumor volume in the three mouse models tested, there was no statistically significant difference in tumor growth between the heat and TTField groups. In IR combination experiments, the MC38 mouse model was chosen since TTFields induced a greater TGD effect in this model. In the first Inovivo experiment, we combined TTFields and radiation therapy, which delayed tumor growth significantly. Following that, we tested the combined efficacy of two rounds of TTFields and radiation treatment. The tumor growth delay was more pronounced after two rounds of TTFields treatment compared to one, which confirms the hypothesis that TTFields treatment induces conditional vulnerability. The results are consistent with observations made by the researchers in the clinic that high compliance patients (who have received more exposure to TTFields) have better prognosis compared to low compliance patients. Our inovivo experiment results not only confirm our earlier in vitro results, but also support the use of TTFields in IR combination therapies. Citation Format: Narasimha Kumar Karanam, Zengfu Shang, Michael D. Story, Debabrata Saha. Tumor Treating Fields in combination with radiation cause significant delay in tumor growth in in-vivo mice modelsignificant delay in tumor growth in in-vivo mice model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3316.