Genetically engineered mouse models of brain cancer and the promise of preclinical testing

Abstract

Recent improvements in the understanding of brain tumor biology have opened the door to a number of rational therapeutic strategies targeting distinct oncogenic pathways. The successful translation of such "designer drugs" to clinical application depends heavily on effective and expeditious screening methods in relevant disease models. By recapitulating both the underlying genetics and the characteristic tumor-stroma microenvironment of brain cancer, genetically engineered mouse models (GEMMs) may offer distinct advantages over cell culture and xenograft systems in the preclinical testing of promising therapies. This review focuses on recently developed GEMMs for both glioma and medulloblastoma, and discusses their potential use in preclinical trials. Examples showcasing the use of GEMMs in the testing of molecularly targeted therapeutics are given, and relevant topics, such as stem cell biology, in vivo imaging technology and radiotherapy, are also addressed.

Figure 1

Glioma‐implicated signaling pathways that have been employed in the production of genetically engineered mouse models. Oncogenes are shown in green, and tumor suppressors are shown in red. Examples of pharmaceutical agents are shown in italicized blue with their targets indicated.

Figure 2

Examples of murine brain tumor models incorporating RCAS/tv‐a technology. A. High‐grade glioma driven by RCAS‐PDGF and RCAS‐Cre in an Ntv‐a; Ink4a/Arf−/−; floxed PTEN background. Black arrows indicate pseudopalisading necrosis, and white arrows highlight foci of microvascular proliferation. B. High‐grade glioma driven by RCAS‐kRAS and RCAS‐Akt in an Ntv‐a; Ink4a/Arf−/− background. Black arrows indicate necrosis. C. Medulloblastoma driven by RCAS‐SHH in an Ntv‐a background. All micrographs were taken at 20× magnification.

Figure 3

SHH signaling pathway components that have been employed in the production of genetically engineered mouse models. Oncogenes are shown in green, and tumor suppressors are shown in red. Examples of pharmaceutical agents are shown in italicized blue with their targets indicated.