Abstract 2417: Liver regeneration after radiation therapy: clinical observations and a new rat model

Abstract Background and Purpose: Radiation-induced liver damage, a dose-limiting complication of radiotherapy for liver tumors, has been focused mainly on prevention and treatment but has largely ignored the molecular mechanisms underlying the liver’s regenerative capacity after irradiation. Whether liver regeneration compensates for radiation-induced liver damage is of great clinical significance. This study aims to observe clinical liver regeneration and the potential molecular mechanism in rat models after irradiation. Methods: To stimulate the liver regeneration response, we delineated a liver protection area in the patient’s normal liver to protect it from excessive irradiation, and designed a rat model in which large single fractions of 25 Gy or 15 Gy of radiation were delivered to 1/2 or 2/3 of the total liver volume to investigate liver regeneration after irradiation. We used proteomics analysis and western blotting assays to investigate liver regeneration signaling and molecular mechanisms. Results: Four patients’ pairs of liver specimens from areas of high irradiation and regeneration (protected liver) were collected. Proteomics analysis showed enrichment in several pathways, with some of the greatest changes observed in PI3K-Akt signaling, further confirmed in liver-irradiated rat models. After irradiation, the liver injury index was significantly elevated on day-1 and gradually recovered to normal levels by day-8 in rat models. The model of a single 25-Gy fraction delivered to half of the liver volume best represented the clinically similar phenomenon of liver regeneration in the protected liver. We tested the effects of an Akt/mTOR activator (carbamazepine), which enhanced regeneration, and an Akt/mTOR inhibitor (temsirolimus), which inhibited regeneration. Finally, liver regeneration was enhanced in rats treated with temsirolimus followed by carbamazepine. Conclusions: Our results suggest that protecting the normal liver outside the irradiated area enhances the probability of successful regeneration to compensate for radiation-induced liver injury. PI3K/AKT/mTOR is essential in liver regeneration after irradiation, and carbamazepine may enhance liver regeneration after irradiation in rats. Citation Format: Tingshi Su, Weidong Zhao, qing Li, Qiaoyuan Wu. Liver regeneration after radiation therapy: clinical observations and a new rat model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2417.