CDK4/6 and PDGFRA Signaling as Therapeutic Targets in Diffuse Intrinsic Pontine Glioma

Abstract

Diffuse intrinsic pontine gliomas (DIPGs) are incurable childhood brain tumors, whereby the standard of care is focal radiation, a treatment that provides temporary relief for most patients. Surprisingly, decades of clinical trials have failed to identify additional therapies that can prolong survival in this disease. In this conference manuscript, we discuss how genetic engineered mouse modeling techniques with the use of a retroviral gene delivery system can help dissect the complex pathophysiology of this disease. With this approach, autochthonous murine DIPG models can be readily induced to (1) help interrogate the function of novel genetic alterations in tumorigenesis, (2) identify candidate cells of origin for this disease, (3) address how region-specific differences in the central nervous system influence the process of gliomagenesis, and (4) evaluate novel therapeutics in an immunocompetent model.

Keywords: CDK4/6; K27M; PDGF-A; PDGFRA; diffuse intrinsic pontine glioma; platelet-derived growth factor-B.

Figure 1

Common genetic alterations in human diffuse intrinsic pontine gliomas (DIPGs) and a schematic illustrating how the RCAS/tumor virus A (TVA) system is used to induce murine DIPGs.

Figure 2

Murine diffuse intrinsic pontine glioma (DIPG) induced by PDGF-A; H3.1K27M; p53 loss. Low (top) and high (bottom) magnification images of a murine DIPG induced with the RCAS/tumor virus A (TVA) system using Nestin TVA; p53 floxed/floxed mice. Neonatal mouse was infected postnatally with DF1 expressing RCAS vectors expressing PDGF-A, H3.1 K27M, and Cre (to delete p53) at a ratio of 1:1:1, and euthanized 43 days’ post-infection. Images from left to right: H&E, Ki-67, HA (tag for H3.1K27M), and Olig2 immunohistochemistry. Note the infiltration into the cerebellum (best seen on low magnification HA and Olig2 immunohistochemistry images).