Abstract 610: Regression of spontaneous non-small cell lung cancers in P53 mutant transgenic mice following exposure to PRIMA-1

Abstract

Abstract P53 mutations are common in lung cancer, thus restoration of p53 function in tumor cells have the potential to be an important approach for lung cancer therapy. The small molecule PRIMA-1 (p53-dependent reactivation and induction of massive apoptosis) has been shown to induce apoptosis in human tumor cells containing mutant p53 by restoration of tumor suppressor function of p53. This is believed to be mediated by a change in the conformation of mutated p53 protein, restoring DNA binding and activation of p53 target genes. We have 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 at an age range of 12-15 months. To evaluate feasibility and preliminary activity of PRIMA-1 on the murine spontaneous lung tumor, 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 two 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. Five mice received the PRIMA-1, and a control group of 4 lung tumor mice received PBS every other day for two weeks. A repeat CT scan was obtained the week after the last treatment. Results of post-treatment with pre-treatment CT volume comparisons are detailed below: These preliminary results indicate activity of PRIMA-1 in lung tumor bearing P53 mutant transgenics, and suggest the potential feasibility of using p53 restoring activity small molecules to treat lung cancer. Expansion of the sample size, as well as mechanistic and dosing studies is ongoing in order to strengthen the rationale to eventually pursue this strategy in clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 610. doi:10.1158/1538-7445.AM2011-610