Abstract 1351: Targeting mutant p53 protein in spontaneous non-small cell lung cancers in transgenic mice

Abstract

Abstract Background: Restoration of p53 function in cancer cells is an important approach for cancer therapy because p53 mutations are found in many human cancers, including lung cancers. An anti-mutant p53 agent, p53 reactivation and induction of massive apoptosis (PRIMA-1) has been used to restore the function of the mutant p53 to its wildtype function. Examination of PRIMA-1-induced tumor suppression has indicated the potential role of microRNAs (miRNAs) in the regulation of oncogene or tumor suppressor gene expression. However, the anti-tumor effect of the PRIMA-1 in the treatment of spontaneous lung cancer is still unclear. Methods: We developed a lung tumor model in transgenic mice in which the human mutant p53(273H) is expressed in a lung-specific manner, under the control of the surfactant protein C promoter. These mice developed lung adenocarcinomas after the age of 12 months. We treated SPC-p53-273H lung tumor-bearing mice via intraperitoneal injection (i.p) with PRIMA-1 at a dose of 100 mg/kg in 0.2 ml PBS every other day for three weeks. Lung tumor-bearing mice were identified with a micro-computed tomography (micro-CT) system and pre-and post-treatment tumor volumes were estimated based on the micro-CT image. miRNA expressions were analyzed with the NanoString nCounter Analysis System. Results: Of the 11 treated mice, micro-CT-derived volume changes indicated that five p53-273H mice were responsive to the PRIMA-1 treatment, with an average volume decrease of 93.55 mm3. Four of the treated mice experienced tumor growth post-treatment, with an average volume increase of 74.96 mm3. The remaining two p53-273H mice did not experience a significant change in tumor size. Compared against the control group, the PRIMA-1 treated p53-273H mice showed an overall decrease in tumor size, with an average tumor volume fold change of -2.33. The untreated controls showed a fold change of 8.16, nearly four times that of the treated cohort. Over 500 microRNA were compared between the treated and the control tumors by the NanoString nCounter array analysis. Seven microRNA were identified to have experienced a significant increase (greater than 2 folds) in expression in response to the PRIMA-1 treatment. Fifty-nine miRNAs displayed a significant decrease in expression (less than -2 folds). Conclusion: The results of the study indicated a significant reduction in tumor size in the mice treated with PRIMA-1, based on micro-CT images. Contrary to this finding, an increased average fold change was seen in the control group, indicating an overall average increase in tumor volume. The results indicate the activity of PRIMA-1 in lung tumor-bearing P53 mutant transgenics and suggest the potential feasibility of using PRIMA-1 (APR-246) to treat lung cancer. In addition, microRNA may potentially be involved in the anti-cancer property of PRIMA-1. Further investigation is needed to elucidate the mechanisms in PRIMA-1 induced apoptosis. Citation Format: Shaylyn Grier, Li Gao, Melanie Perez, Wenrui Duan. Targeting mutant p53 protein in spontaneous non-small cell lung cancers in transgenic mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1351.