Dataset Information

Cutting Edge Therapeutic Insights Derived from Molecular Biology of Pediatric High-Grade Glioma and Diffuse Intrinsic Pontine Glioma (DIPG).

ABSTRACT: Pediatric high-grade glioma (pHGG) and brainstem gliomas are some of the most challenging cancers to treat in children, with no effective therapies and 5-year survival at ~2% for diffuse intrinsic pontine glioma (DIPG) patients. The standard of care for pHGG as a whole remains surgery and radiation combined with chemotherapy, while radiation alone is standard treatment for DIPG. Unfortunately, these therapies lack specificity for malignant glioma cells and have few to no reliable biomarkers of efficacy. Recent discoveries have revealed that epigenetic disruption by highly conserved mutations in DNA-packaging histone proteins in pHGG, especially DIPG, contribute to the aggressive nature of these cancers. In this review we pose unanswered questions and address unexplored mechanisms in pre-clinical models and clinical trial data from pHGG patients. Particular focus will be paid towards therapeutics targeting chromatin modifiers and other epigenetic vulnerabilities that can be exploited for pHGG therapy. Further delineation of rational therapeutic combinations has strong potential to drive development of safe and efficacious treatments for pHGG patients.

SUBMITTER: Bailey CP

PROVIDER: S-EPMC6315414 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Cutting Edge Therapeutic Insights Derived from Molecular Biology of Pediatric High-Grade Glioma and Diffuse Intrinsic Pontine Glioma (DIPG).

Bailey Cavan P CP Figueroa Mary M Mohiuddin Sana S Zaky Wafik W Chandra Joya J

Bioengineering (Basel, Switzerland) 20181018 4

Pediatric high-grade glioma (pHGG) and brainstem gliomas are some of the most challenging cancers to treat in children, with no effective therapies and 5-year survival at ~2% for diffuse intrinsic pontine glioma (DIPG) patients. The standard of care for pHGG as a whole remains surgery and radiation combined with chemotherapy, while radiation alone is standard treatment for DIPG. Unfortunately, these therapies lack specificity for malignant glioma cells and have few to no reliable biomarkers of e ...[more]

PMID: 30340362

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Project description:Abstract PURPOSE: To correlate MR imaging findings with molecular analyses in DIPG. METHODS: Baseline MR imaging studies, including standard pre- and post-contrast MR sequences, were reviewed from patients included in our multi-institutional, IRB-approved DIPG trial NCT01182350. Prospectively acquired imaging data were analyzed after study closure, including FLAIR/T2 tumor volume; tumor volume enhancement and cyst/necrosis; median, mean, mode, skewness, and kurtosis of apparent diffusion coefficient (ADC) tumor volume based on both FLAIR and enhancement at baseline. Whole-genome and RNA-sequencing identified histone mutations. We applied univariate Cox proportional-hazards regression modeling to test the association of imaging predictors with overall (OS) and progression-free survival (PFS). Wilcoxon rank-sum, Kruskal-Wallis, and Fisher’s exact tests compared imaging measures between groups. RESULTS: Fifty patients underwent biopsy and MRI. Median age at trial registration was 6 years (range,3.3–17.5 years); 52% of patients were female. Molecular subgroup study assignments for 48 patients’ tumors were as follows: 28 in MGMT-/EGFR-, 14 in MGMT-/EGFR+, 3 in MGMT+/EGFR-, and 3 in MGMT+/EGFR+. Further genetic testing identified mutations in histones, PDGFRA, ACVR1, TP53, EGFR, PPM1D, FGFR, and/or PI3K. Twenty-three tumors possessed histone mutations in H3F3A, 8 in HIST1H3B, and 3 in HISTH3C. Median follow-up time was 11 months (range,0.4–33 months). Poorer OS (p=0.01) and PFS (p=0.001) were significantly associated with increased enhancing tumor volume. Enhancing tumor volume also differed significantly across molecular subgroups (p=0.047). Tumor enhancement, mode, skewness, and kurtosis ADC-FLAIR differed significantly (p?0.048) between patients with H3F3A and HIST1H3B mutations. Tumor enhancement, median, mode, skewness, and kurtosis ADC-FLAIR also differed significantly (p?0.048) between patients with H3F3A and HIST1H3B or HISTH3C mutations. CONCLUSIONS: MR imaging features including enhancement and ADC histogram parameters correlate to molecular subgroups in DIPG. Further studies are required to verify and refine these findings in a larger cohort.

Dataset Information

Cutting Edge Therapeutic Insights Derived from Molecular Biology of Pediatric High-Grade Glioma and Diffuse Intrinsic Pontine Glioma (DIPG).

Publications

Cutting Edge Therapeutic Insights Derived from Molecular Biology of Pediatric High-Grade Glioma and Diffuse Intrinsic Pontine Glioma (DIPG).

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