Abstract 4187: A rapid and robust transgenic high-grade glioma mouse model for therapy-intervention studies

Abstract

Abstract High-grade glioma is a devastating and uniformly fatal disease for which better therapy is urgently needed. Glioma cells extensively infiltrate into surrounding pivotal brain structures, thereby rendering current treatments largely ineffective. Evaluation of novel therapies requires the availability of appropriate glioma mouse models. We here present a novel transgenic mouse model of high-grade glioma that can be conveniently used for testing therapy-intervention strategies. High-grade gliomas were induced by stereotactic intracranial injection of self-deleting lentiviral GFAP-Cre or CMV-Cre vectors into adult immune-competent compound LoxP-conditional mice, resulting in localized expression of K-Rasv12 in conjunction with loss of p16Ink4a/p19Arf with or without concomitant loss of p53 or Pten. Tumors have been characterized by histology, immune-histochemistry and magnetic resonance imaging and reproduced many of the features that are characteristic for human high-grade gliomas, including invasiveness and blood-brain barrier functionality. We are currently assessing which molecular alterations in cell signaling pathways have occurred. Especially CMV-Cre injection into p53;Ink4a/Arf;K-Rasv12 mice resulted in grade IV (glioblastoma multiforme) with a short tumor latency (2-3 weeks) and full penetrance. Early detection and follow-up of tumor growth can be accomplished conveniently by non-invasive bioluminescence imaging and the practical utility for therapy-intervention has been demonstrated in a study with temozolomide. Temozolomide delayed tumor progression modestly but significantly in line with what is observed in patients. Importantly, this novel model can be used with almost the same convenience as traditional xenograft models, thus allowing the implementation of realistic high grade glioma models at the forefront of preclinical evaluation. We expect that this model will be particularly useful to assess the potential clinical utility of agents that may augment temozolomide cytotoxicity, such as PARP-inhibitors or Wee1 kinase inhibitors, but also for agents targeting activated RAS and/or PI3K-Akt-mTor signaling pathways. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4187.