Abstract
Diffuse Midline Gliomas with Histone 3-Lysine-27-Methionine (H3K27M) mutation constitute the majority of Diffuse Intrinsic Pontine Glioma (DIPG), which is the most aggressive form of pediatric glioma with a dire prognosis. DIPG are lethal tumors found in younger children with a median survival <1 year from diagnosis. Discovery of the characteristic H3K27M mutations offers opportunity and hope for development of targeted therapies for this deadly disease. The H3K27M mutation, likely through epigenetic alterations in specific H3 lysine trimethylation levels and subsequent gene expression, plays a significant role in pathogenesis of DIPG. Animal models accurately depicting molecular characteristics of H3K27M DIPG are important to elucidate underlying pathologic events and for preclinical drug evaluation. Here we review the past and present DIPG models and describe our efforts developing patient derived cell lines and xenografts from pretreated surgical specimens. Pre-treated surgical samples retain the characteristic genomic and phenotypic hallmarks of DIPG and establish orthotopic tumors in the mouse brainstem that recapitulate radiographic and morphological features of the original human DIPG tumor. These models that contain the H3K27M mutation constitute a valuable tool to further study this devastating disease and ultimately may uncover novel therapeutic vulnerabilities.
Highlights
Brain tumors are the leading cause of cancer death in children
Since other researchers (Caretti et al.) have previously reported that human Diffuse Intrinsic Pontine Glioma (DIPG) xeno-transplatation may lead to induction of murine tumors resembling DIPG tumors [26], we carefully examined the origin of these tumor cells
WP1066 significantly reduced H3K27M PED17-G-L tumor growth in orthotopic xenografts compared to control at 8 weeks (Figure 2I). These results demonstrate the utility of orthotopic xenograft models and provide rationale for clinical evaluation of WP1066 in patients with DIPG
Summary
Brain tumors are the leading cause of cancer death in children. About 10% of pediatric brain tumors are primary brainstem tumors classified into four categories: diffuse, focal intrinsic, focal exophytic, and cervico-medullary glioma [1]. Monje and colleagues stereotactically implanted patient-derived DIPG tumor cells into the pons of non-obese diabetic/SCID/γchain null–immuno-deficient mice to create the first patientderived DIPG xenograft model [19]. An early GEMM model of DIPG was generated using the replication-competent avian sarcoma-leucosis virus (RCAS) vector to enable Ink4a-ARF loss and platelet-derived growth factor B (PDGFB) overexpression within nestin-expressing cells in the pons of genetically engineered pups expressing tumor virus A (TVA) under the nestin promoter.
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