Abstract 6282: Olaparib in combination with hemithoracic radiation increases the therapeutic index in a urethane-induced mouse lung cancer model

Abstract

Abstract Purpose: The radiosensitizing effect of the Poly (ADP-ribose) polymerase (PARP) inhibitor olaparib on tumors has been reported in preclinical models. However, its effect on normal tissue toxicity following thoracic radiation have not been well studied. Herein, we investigated the therapeutic index of olaparib combined with hemithoracic radiation after early or late intervention in a urethane-induced lung cancer model. Methods and Materials: Female A/J mice were treated with 5% urethane (i.p.) to induce lung tumors. To assess tolerability, mice first received 13 Gy whole thorax radiation in combination with olaparib (100 mg/kg, p.o.) or vehicle, 1 h before and 2 h after radiation. Body weight was monitored and esophagi were collected 2 wks after treatment. In the early intervention study, treatment started at 8 weeks after urethane injection, mice were treated with olaparib (50 mg/kg, p .o.) or hemithorax irradiation (5 × 5 Gy on left lung) alone and in combination. Mice were sacrificed at 24 wks after radiation treatment. Lung fibrosis was assessed by Masson's Trichrome staining and α-SMA IHC. In the late intervention study, treatment started at 18 weeks after urethane injection. Mice were treated with olaparib (100 mg/kg, p.o.) or hemithorax irradiation (13 Gy on left lung) alone and in combination. Lung tumor growth was monitored by MRI. Mice were sacrificed at 6 wks after radiation treatment. Superficial lung tumors were counted and lung sections were processed for histology. Results: Enhanced body weight loss and evidence of esophageal toxicity were observed when olaparib was combined with whole thorax but not with hemithorax radiation. In the early intervention study, olaparib did not enhance radiation-induced lung fibrosis. However, olaparib plus hemithorax radiation significantly reduced the tumor burden in left lungs compared to radiation alone (total tumor number: p<0.05, tumor volume: p<0.05, surface tumor number: p<0.0001). Similar to the early intervention study, late intervention with olaparib and hemithorax radiation was well-tolerated and also significantly decreased tumor burden compared to hemithorax radiation treatment alone (p<0.05). Conclusions: Our data demonstrate that combination treatment with olaparib and can increase the effectiveness of hemithorax radiation in a urethane-induced lung cancer model in both early and late intervention settings without increasing normal tissue toxicity. Our study provides preclinical support for the ongoing clinical trials of PARP inhibitors in combination with thoracic radiation for lung cancer. Citation Format: Yanyan Jiang, Anderson Ryan. Olaparib in combination with hemithoracic radiation increases the therapeutic index in a urethane-induced mouse lung cancer model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6282.