Targeting CD133 improves chemotherapeutic efficacy of recurrent pediatric pilocytic astrocytoma following prolonged chemotherapy

Quantification of western blot results showing overexpression of pAKT(S473, T308) and pNF-ƙB/p65 in recurrent PAs with chemotherapy, compared to matched primary tumors. (TIF 52 kb

Therapeutic Potential for Bone Morphogenetic Protein 4 in Human Malignant Glioma

Human glioma, in particular, malignant forms such as glioblastoma exhibit dismal survival rates despite advances in treatment strategies. A population of glioma cells with stem-like features, glioma cancer stem-like cells (GCSCs), contribute to renewal and maintenance of the tumor cell population and appear responsible for chemotherapeutic and radiation resistance. Bone morphogenetic protein 4 (BMP4), drives differentiation of GCSCs and thus improves therapeutic efficacy. Based on this observation it is imperative that the clinical merits of BMP4 in treating human gliomas should be addressed. This article reviews BMP4 signaling in central nervous system development and in glioma tumorigenesis, and the potential of this molecule as a treatment target in human gliomas. Further work needs to be done to determine if distinct lineages of GCSCs, associated with different glioma sub-classifications, proneural, neural, classical and mesenchymal, differ in responsiveness to BMP4 treatment. Additionally, interaction among BMP4 and cell matrix, tumor-vascular molecules and microglial immune cells also needs to be investigated, as this will enhance our knowledge about the role of BMP4 in human glioma and lead to the identification and/or development of novel therapeutic approaches that improve treatment outcomes of these devastating tumors

Advanced Pediatric Diffuse Pontine Glioma Animal Models Pave the Way Towards Precision Medicine

Diffuse intrinsic pontine gliomas (DIPGs) account for ~15% of pediatric brain tumors, which invariably present with poor survival regardless of treatment mode. Several seminal studies have revealed that 80% of DIPGs harbor H3K27M mutation coded by HIST1H3B, HIST1H3C and H3F3A genes. The H3K27M mutation has broad effects on gene expression and is considered a tumor driver. Determination of the effects of H3K27M on posttranslational histone modifications and gene regulations in DIPG is critical for identifying effective therapeutic targets. Advanced animal models play critical roles in translating these cutting-edge findings into clinical trial development. Here, we review current molecular research progress associated with DIPG. We also summarize DIPG animal models, highlighting novel genomic engineered mouse models (GEMMs) and innovative humanized DIPG mouse models. These models will pave the way towards personalized precision medicine for the treatment of DIPGs.</jats:p

Advanced Pediatric Diffuse Pontine Glioma Murine Models Pave the Way towards Precision Medicine

Diffuse intrinsic pontine gliomas (DIPGs) account for ~15% of pediatric brain tumors, which invariably present with poor survival regardless of treatment mode. Several seminal studies have revealed that 80% of DIPGs harbor H3K27M mutation coded by HIST1H3B, HIST1H3C and H3F3A genes. The H3K27M mutation has broad effects on gene expression and is considered a tumor driver. Determination of the effects of H3K27M on posttranslational histone modifications and gene regulations in DIPG is critical for identifying effective therapeutic targets. Advanced animal models play critical roles in translating these cutting-edge findings into clinical trial development. Here, we review current molecular research progress associated with DIPG. We also summarize DIPG animal models, highlighting novel genomic engineered mouse models (GEMMs) and innovative humanized DIPG mouse models. These models will pave the way towards personalized precision medicine for the treatment of DIPGs.</jats:p

PATH-07. SIGNIFICANCE OF H3K4me3 IN PEDIATRIC HIGH-GRADE GLIOMAS

Abstract Pediatric high-grade gliomas (pHGGs) account for ~20% of childhood brain tumors, are incurable in nearly all instances, and have an average patient survival of less than 15 months. Histone posttranslational modifications (PTMs) are deregulated in pHGGs. There are many gaps in our knowledge regarding the mechanisms by which “normal” PTM is subverted during pHGG development. Preliminary results from our lab show pHGGs are enriched in H3K4me3 and that the extent of this specific PTM is predictive of patient survival length. H3K4me3 levels are controlled by methyltransferase and demethylase activity. Gene expression analysis indicates SETD1A and WDR82, enzymatic subunits of human SETD1A containing methyltransferase complex (referred to as hSETD1A-COMPASS), are responsible for H3K4 methylation. SETD1A and WDR82 are significantly elevated in pHGGs, relative to pediatric low-grade gliomas (pLGGs), and both show a direct association with glioma malignancy. Interestingly, these associations do not exist in adult gliomas. The results suggest that hSETD1A-COMPASS specifically impacts pHGG development and is a potential therapeutic target for these tumors.</jats:p

Pediatric Suprasellar Germ Cell Tumors: A Clinical and Radiographic Review of Solitary vs. Bifocal Tumors and Its Therapeutic Implications

Suprasellar germ cell tumors (S-GCTs) are rare, presenting in either solitary or multifocal fashion. In this study, we retrospectively examine 22 solitary S-GCTs and 20 bifocal germ cell tumors (GCTs) over a 30-year period and demonstrate clinical, radiographic, and prognostic differences between the two groups with therapeutic implications. Compared to S-GCTs, bifocal tumors were almost exclusively male, exhibited higher rate of metastasis, and had worse rates of progression free and overall survival trending toward significance. We also introduce a novel magnetic resonance (MR) imaging classification of suprasellar GCT into five types: a IIIrd ventricle floor tumor extending dorsally with or without an identifiable pituitary stalk (Type Ia, Ib), ventrally (Type III), in both directions (Type II), small lesions at the IIIrd ventricle floor extending to the stalk (Type IV), and tumor localized in the stalk (Type V). S-GCTs almost uniformly presented as Type I–III, while most bifocal GCTs were Type IV with a larger pineal mass. These differences are significant as bifocal GCTs representing concurrent primaries or subependymal extension may be treated with whole ventricle radiation, while cerebrospinal fluid (CSF)-borne metastases warrant craniospinal irradiation (CSI). Although further study is necessary, we recommend CSI for bifocal GCTs exhibiting high-risk features such as metastasis or non-germinomatous germ cell tumor histology.</jats:p