Abstract 2854: Delineation of grade-specific molecular drivers in inducible preclinical mouse models of astrocytoma

Abstract

Abstract Glioblastoma (GBM) is a uniformly lethal neoplasm that accounts for 20% of all primary brain tumors. Despite advances in multimodality therapy, the median survival for patients with this disease remains approximately 12 months and has changed little over the past 40 years. An increased understanding of the molecular genetic basis of gliomagenesis is urgently required to develop more effective therapies for this devastating disease. Recently, The Cancer Genome Atlas (TCGA) project reported the most extensive genetic analysis of GBMs enhancing our ability to query altered signaling pathways potentially involved. Yet, an understanding of disease etiology requires extensive modeling in mammalian genetic systems coupled with analyses of biological contributions of disease. Here we genetically perturbed the primary molecular pathways (pRb and Ras) in genetically engineered mouse models (GEM). Alterations were induced specifically in adult GEM astrocytes via a tamoxifen-inducible, human GFAP promoter-driven CreERTM allele. GEM with astrocyte RB pathway inactivation alone (T) developed low-grade astrocytomas (grade II). Constitutive KRAS activation alone (R) did not produce detectable brain pathology. GEM harboring both inactivated RB and constitutively active KRAS (TR) in astrocytes developed high-grade astrocytomas (grade III) with low frequency of GBM development (grade IV). Deletion of Pten further progressed the tumor to grade IV with high frequency. Mechanistically, pRb inactivation led to activation of MAPK pathway via Ras. Mutant Kras did not further activate MAPK. Instead, it activated PI3K pathway. Deletion of Pten further activated PI3K-AKT pathway, leading to higher GBM rate. These highly penetrant, inducible GEM models provide a unique system for delineating the downstream pathways and resulting biological abnormalities critical to astrocytoma pathogenesis and for preclinical drug and biomarker development. Initial studies have begun to define the relative contribution to disease of each disrupted pathway, including potential targets for therapeutic intervention. 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 2854. doi:10.1158/1538-7445.AM2011-2854