Approaches Toward Improving the Prognosis of Pediatric Patients With Glioma: Pursuing Mutant Drug Targets With Emerging Small Molecules

Gliomas represent approximately 70% of all pediatric brain tumors and most of these are of astrocytic lineage, furthermore, malignant or high-grade astrocytoma account for approximately 20% of pediatric astrocytoma. Treatment options for pediatric glioma patients are limited. Although low-grade astrocytoma are relatively slow-growing tumors which can often be cured through surgical resection, a significant proportion of cases will recur, as such new treatments are desperately needed. This review covers the various approaches that are currently being made towards improving the prognosis of pediatric glioma patients by pursuing pediatric-selective mutant drug targets with emerging small molecules

Preliminary SAR on indole-3-carbinol and related fragments reveals a novel anticancer lead compound against resistant glioblastoma cells

The prognosis for glioblastoma patients is, at best, poor, with the median time of survival after diagnosis measured in months. As such, there is much need for the rapid development of potent and novel treatments. Herein, we report our preliminary findings on the SAR of a series of indole-3-carbinol and related fragments and reveal a potent lead with low micromolar activity against a particularly resistant glioblastoma cell culture, providing a new platform for future development of a new therapy in this area

The GALNT9, BNC1 and CCDC8 genes are frequently epigenetically dysregulated in breast tumours that metastasise to the brain.

Tumour metastasis to the brain is a common and deadly development in certain cancers; 18-30 % of breast tumours metastasise to the brain. The contribution that gene silencing through epigenetic mechanisms plays in these metastatic tumours is not well understood

A Prominin-1-Rich Pediatric Glioblastoma: Biologic Behavior Is Determined by Oxygen Tension-Modulated CD133 Expression but Not Accompanied by Underlying Molecular Profiles12

Few studies on the biologic and molecular properties of pediatric glioblastoma have been performed. Until now, differential genomic analysis of CD133+ve and CD133-ve fractions has not been described in pediatric glioma. We hypothesize not only that the presence of CD133 could be the source of tumor resistance but also that maintenance of this molecule by hypoxia dictates cellular and molecular behavior. From a series of human glioblastoma biopsies investigated, only one, IN699 (from a pediatric glioblastoma), generated greater than 4% of the total cell volume as CD133+ve cells. Using this pediatric glioblastoma, containing unprecedented high levels of the putative brain tumor stem cell marker CD133, as a study model, we report biologic and molecular characteristics of the parent culture and of CD133+ve and CD133-ve populations derived therefrom under atmospheric and hypoxic culture conditions. Immunocytochemistry and flow cytometry were performed with antigenic markers known to characterize neural stem cells and associated glioma behavior. Behavioral analysis was carried out using proliferation, adhesion, migration, and invasion assays. Cell cycle analysis and array comparative genomic hybridization were used to assess copy number profiles for parental cells and CD133+ve and CD133-ve fractions, respectively. With regard to invasion and proliferation, CD133+ve and CD133-ve fractions were inversely proportional, with a significant increase in invasive propensity within the CD133-ve cells (P < .005) and a significant increase in proliferation within CD133+ve cells (P < .005). Our observations indicate identical genomic imbalances between CD133+ve and CD133-ve fractions. Furthermore, our research documents a direct link between decreasing oxygen tension and CD133 expression

Trawling disturbance can modify benthic production processes

1. Trawling disturbance has wide-ranging impacts on the marine environment and is well known to modify benthic habitat and community structure. This has led to speculation about the positive and negative impacts of trawling on ecosystem processes such as production. 2. Existing theory suggests that frequent trawling disturbance may lead to the proliferation of smaller benthic species, with faster life histories, because they can withstand the mortality imposed by trawling and benefit from reduced competition or predation as populations of larger species are depleted. Since smaller species are more productive, trawling disturbance may 'farm the sea', with knock-on benefits for consumers, including fish populations. 3. We conducted the first large-scale studies of trawling effects on benthic production across quantified gradients of trawling disturbance on real fishing grounds in two regions (Silver Pit and Hills) of the North Sea. There were 27- and 10-fold differences in levels of beam trawl disturbance among the Silver Pit and Hills sites, respectively. 4. Size structure was described using normalized size-spectra, and the slopes and intercepts of these spectra were related to levels of trawling disturbance. Production was estimated from the size spectra, using a new allometric relationship between body mass and the production to biomass (P:B) ratio of marine invertebrates. The general validity of the relationship was confirmed using a phylogenetic comparative approach. 5. In the Silver Pit region, trawling led to significant decreases in infaunal biomass and production. The abundance of larger individuals was depleted more than smaller ones, as reflected by the positive relationship between the slope of the normalized size spectra and trawling disturbance. The effects of trawling disturbance were not significant in the epifaunal community. In the Hills region, where the range of trawling disturbance was lower, trawling disturbance did not have significant effects on biomass or production. 6. In the Silver Pit, relative infaunal production (production per unit biomass) rose with increased trawling disturbance. This was attributable largely to the dominance of smaller animals in the disturbed communities. The increase in relative production did not compensate for the loss of total production that resulted from the depletion of large individuals. There was some evidence for the proliferation of small polychaetes at moderate levels of disturbance, but at higher levels of disturbance their biomass and production fell. 7. We conclude that reported increases in the biomass and production of small infaunal invertebrates in the North Sea are attributable largely to recent increases in primary production that were driven by climate change, and not to the effects of trawling disturbance

In: Abstracts for the Eleventh Annual Meeting of the Society for Neuro-Oncology: November 16–19, 2006. PE-16

Abstracts from Neuro-Oncology are provided here courtesy of Society for Neuro-Oncology and Duke University PressBrain tumors are the most frequently found solid tumor in children, 40% of which are astrocytomas. These are graded according to the WHO classification into the more common low-grade (I and II) and high-grade (III and IV) tumors. Little is known about the genetic basis underlying the development of pediatric astrocytomas. In this study, we have studied the correlation between abnormal gene expression in pediatric astrocytoma with genomic copy number changes. We used the Affymetrix HGU133A array to identify differentially expressed genes in a group of pediatric astrocytoma short-term cell cultures comprising 9 grade I, 11 grade II and 12 grade IV tumors. Data analysis was carried out using Genespring version 6.0 software. In addition, we used the Spectral Chip 2600 to generate array-comparative genomic hybridization (aCGH) profiles of each short-term cell culture. Chromosome regions of gain and loss were then compared with differential gene expression using Formatter software. Hierarchical clustering of the short-term cultures according to expression profile similarity showed that the tumors clustered into 3 clear groups that were independent of grade. Two groups were predominantly low-grade tumors, comprised of a mixture of grade I and II tumors with 3 grade IV tumors, and the third group contained predominantly high-grade tumors with 2 low-grade tumors. Genes involved in the phosphatidylinositol signaling system, the cell cycle pathway, and the regulation of the actin cytoskeleton, were significantly differentially expressed between the 3 groups. Differential disruption of these cell pathways may be associated with subtypes of pediatric astrocytoma. Most tumors in the third group (including the low-grade tumors) showed copy number changes that can be correlated with changes in gene expression. In specific tumors, the downregulation of TSB1 (thrombospondin-1) correlated with loss at 15q15. This gene has previously been found to be downregulated in astrocytoma and is involved in cell adhesion. This finding suggests that gene expression in a subset of pediatric astrocytomas is influenced by gene dosage

Genomic Deletions Correlate with Underexpression of Novel Candidate Genes at Six Loci in Pediatric Pilocytic Astrocytoma1

The molecular pathogenesis of pediatric pilocytic astrocytoma (PA) is not well defined. Previous cytogenetic and molecular studies have not identified nonrandom genetic aberrations. To correlate differential gene expression and genomic copy number aberrations (CNAs) in PA, we have used Affymetrix GeneChip HG_U133A to generate gene expression profiles of 19 pediatric patients and the SpectralChip 2600 to investigate CNAs in 11 of these tumors. Hierarchical clustering according to expression profile similarity grouped tumors and controls separately. We identified 1844 genes that showed significant differential expression between tumor and normal controls, with a large number clearly influencing phosphatidylinositol and mitogen-activated protein kinase signaling in PA. Most CNAs identified in this study were single-clone alterations. However, a small region of loss involving up to seven adjacent clones at 7q11.23 was observed in seven tumors and correlated with the underexpression of BCL7B. Loss of four individual clones was also associated with reduced gene expression including SH3GL2 at 9p21.2-p23, BCL7A (which shares 90% sequence homology with BCL7B) at 12q24.33, DRD1IP at 10q26.3, and TUBG2 and CNTNAP1 at 17q21.31. Moreover, the down-regulation of FOXG1B at 14q12 correlated with loss within the gene promoter region in most tumors. This is the first study to correlate differential gene expression with CNAs in PA

Genome-wide methylation analyses identifies Non-coding RNA genes dysregulated in breast tumours that metastasise to the brain

© (2022) The Authors. Published by Springer Nature. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1038/s41598-022-05050-zBrain metastases comprise 40% of all metastatic tumours and breast tumours are among the tumours that most commonly metastasise to the brain, the role that epigenetic gene dysregulation plays in this process is not well understood. We carried out 450K methylation array analysis to investigate epigenetically dysregulated genes in breast to brain metastases (BBM) compared to normal breast tissues (BN) and primary breast tumours (BP). For this, we referenced 450K methylation data for BBM tumours prepared in our laboratory with BN and BP from The Cancer Genome Atlas. Experimental validation on our initially identified genes, in an independent cohort of BP and in BBM and their originating primary breast tumours using Combined Bisulphite and Restriction Analysis (CoBRA) and Methylation Specific PCR identified three genes (RP11- 713P17.4, MIR124-2, NUS1P3) that are hypermethylated and three genes (MIR3193, CTD-2023M8.1 and MTND6P4) that are hypomethylated in breast to brain metastases. In addition, methylation differences in candidate genes between BBM tumours and originating primary tumours shows dysregulation of DNA methylation occurs either at an early stage of tumour evolution (in the primary tumour) or at a later evolutionary stage (where the epigenetic change is only observed in the brain metastasis). Epigentic changes identified could also be found when analysing tumour free circulating DNA (tfcDNA) in patient’s serum taken during BBM biopsies. Epigenetic dysregulation of RP11-713P17.4, MIR3193, MTND6P4 are early events suggesting a potential use for these genes as prognostic markers