Abstract 4740: Establishment of P53 mutant type specific spontaneous lung tumor in transgenic mice for treatment
Authors: Wenrui Duan, Li Gao, Christopher Brooks, Arjun Kalvala, xin wu, Gregory A. Otterson, Miguel A. Villalona-Calero
Journal: Cancer Research (2012)

Abstract Mutant p53 can be classified into two major types, the type I (contact) mutation and type II (conformational) mutation. Important differences between these types have been established, including a higher oncogenic potential for the type II mutation, and the conservation of some wild type activity for type I. To investigate the role of typeI and II p53 mutant in lung tumorigenesis, two transgenic mouse models with human mutant p53(type I,273H and type II, 175H) were developed. To evaluate feasibility of treatment, we treated the SPC-p53(273H) tumor baring mice with PRIMA-1, a small molecule which has been shown to induce apoptosis in human tumor cells containing mutant p53. To evaluate lung tumor rate and age of onset of the type I and II transgenic mice, we evaluated 108 non-transgenic mice, 159 SPC-p53(273H) and 160 SPC-p53(175H) transgenic mice at age of 4-15 months. Among the 108 non-transgenic mice, no tumors were observed among 44 mice in the 4-6 months and 7-9 months groups combined; 2/31 and 2/33 in the 10-12 and 13-15 month groups. Among the 159 type I transgenic mice, lung tumors per age group were observed as follows: 1/29 at 4-6 months; 1/20 at 7-9 months; 5/59 at 10-12 months; 13/51 at 13-15 months. Among the 160 type II mice, tumor developed in 2/14 at 4-6 months; 5/23 at 7-9 months; 14/59 at 10-12 months and 20/64 at 13-15 months. All tumors were identified histopathologically as adenocarcinomas. 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. Twelve tumor bearing mice were received the PRIMA-1 and a control group of 13 lung tumor mice were received PBS only. Among the PRIMA-1 treated group, responses of the PRIMA-1 treated mice were five stability (decreasing less than 50% to growing less than 25% in tumor volume), 3 partial responses (more than 50% reduction in tumor volume), and 4 progressions (25% or greater increase in tumor volume). In the control group, responses were 11 progressions and 2 stabilities. Compared to the type I (273H) mice and the non-transgenic control group at age of 4-15 months, the type II mice have a higher lung tumor incidence statistically (non-trasgenic/175H, p&amp;lt;0.001, 273H/175H, p=0.017, Fisher's exact test). The type II mutant p53 has a higher oncogenic potential than the type I mutant protein in the lung specific transgenic mice. Furthermore, these animal models provide a framework to further evaluation of the effects of these mutations on response to novel anti anticancer treatment interventions. These mice develop a single-lung tumor that is easy to follow and they survive for more than 18 months, providing sufficient time for evaluation of therapeutic strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4740. doi:1538-7445.AM2012-4740