Dataset Information

Clinical outcome in pediatric glial and embryonal brain tumors correlates with in vitro multi-passageable neurosphere formation.

ABSTRACT: Cultured brain tumors can form neurospheres harboring tumorigenic cells with self renewal and differentiation capacities. Renewable neurosphere formation has clinical predictive value in adult malignant gliomas, yet its prognostic role for pediatric brain tumors is unknown.Established neurosphere conditions were used for culturing samples from glial, embryonal and mixed glioneuronal tumors from 56 pediatric patients. Potential associations between neurosphere formation and clinical outcome were analyzed retrospectively.Thirty-seven percent of all samples formed renewable neurospheres. Analysis of available clinical outcome data from 51 patients demonstrated significantly increased hazard ratios (HR) for both disease progression (HR = 9.9, P < 0.001) and death (HR = 16.6, P < 0.01) in the neurosphere forming group. Furthermore, neurosphere formation correlated with adverse progression free survival (PFS) in glial and embryonal tumors, but not in mixed glioneuronal tumors. Overall survival (OS) was significantly worse for neurosphere-forming patients with embryonal tumors, as a group and amongst the subgroup with medulloblastoma, but not in the glial group. Multivariate analysis showed that neurosphere formation was associated with diminished PFS and OS independent of age, gender, or treatment. Neurosphere formation was an independent predictor of diminished PFS of glial tumors after adjusting for grade. Multivariate analysis, adjusting for both Ki67 staining and neurosphere formation, demonstrated that neurosphere formation remained predictive of progression whereas Ki67 did not.Neurosphere formation is more predictive of pediatric brain tumor progression than semi-quantitative Ki67 staining. Pediatric brain tumor derived neurospheres may provide a predictive model for preclinical explorations.

SUBMITTER: Panosyan EH

PROVIDER: S-EPMC4017922 | biostudies-other | 2010 Oct

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Clinical outcome in pediatric glial and embryonal brain tumors correlates with in vitro multi-passageable neurosphere formation.

Panosyan Eduard H EH Laks Dan R DR Masterman-Smith Michael M Mottahedeh Jack J Yong William H WH Cloughesy Timothy F TF Lazareff Jorge A JA Mischel Paul S PS Moore Theodore B TB Kornblum Harley I HI

Pediatric blood & cancer 20101001 4

<h4>Background</h4>Cultured brain tumors can form neurospheres harboring tumorigenic cells with self renewal and differentiation capacities. Renewable neurosphere formation has clinical predictive value in adult malignant gliomas, yet its prognostic role for pediatric brain tumors is unknown.<h4>Methods</h4>Established neurosphere conditions were used for culturing samples from glial, embryonal and mixed glioneuronal tumors from 56 pediatric patients. Potential associations between neurosphere f ...[more]

PMID: 20589659

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

Project description:Abstract BACKGROUND: In previous work we established that PLK4 is overexpressed and essential for proliferation and survival of pediatric embryonal brain tumors. PLK4 is a cell cycle-regulated protein recruited at the centrosome in dividing cells. Its overexpression triggers centrosome amplification, which is associated with genetic instability and carcinogenesis. We demonstrated that PLK4 inhibition exerts a potent cytostatic effect in EBT. We also established the synergism of the PLK4 inhibitor CFI-400945 with cytotoxic drugs and other signal transduction modulators. METHODS: We studied protein kinase inhibitors (PKI) with PLK4 cross-over potential (CFI-400945, CFI-400437, centrinone, centrinone-B, R-1530, axitinib, alisertib and KW-2449) by assessing their chemical profiles through docking simulations over PLK4 (PDB entry: 3COK) using Gold 5.4 software; evaluating their potential to penetrate the BBB (via logBB calculation by Clark equation), performing LanthaScreen EU Kinase Binding assays (ThermoFisher Scientific) and cell based studies (viability and proliferation) in multiple embryonal tumor cell lines (MON, BT-12, BT-16, DAOY, D283). RESULTS: Kinase binding assays and cell based studies showed that CFI-400437 was the most effective compound, yielding an IC50 <5nM in the binding assay and requiring <100nM of drug to significantly inhibit proliferation in multiple cell lines. However, docking simulations using the PLK4 catalytic cavity and each of the various PKIs demonstrated that all of the inhibitors tested exhibit similar interactions within the binding cavity, engaging in H-bonding with backbone residues Glu-89 and Cys-91. Additional polar and hydrophobic (?-stacking) interactions were also identified for each of the PKIs. LogBB calculations revealed that compound R-1530 has the greatest likelihood to enter the brain (LogBB+0.130). CONCLUSION: Although CFI-400945 is the most effective PLK4 inhibitor among those assayed, it has low potential for BBB exposure. Molecular docking results indicate the potential to develop new chemical entities with higher BBB exposure potential using a similar binding mode to that of CFI-400945.

Project description:BackgroundPediatric embryonal brain tumors (PEBTs), which encompass medulloblastoma (MB), primitive neuroectodermal tumor (PNET) and atypical teratoid/rhabdoid tumor (AT/RT), are the second most prevalent pediatric brain tumor type. AT/RT is highly malignant and is often misdiagnosed as MB or PNET. The distinction of AT/RT from PNET/MB is of clinical significance because the survival rate of patients with AT/RT is substantially lower. The diagnosis of AT/RT relies primarily on morphologic assessment and immunohistochemical (IHC) staining for a few known markers such as the lack of INI1 protein expression. However, in our clinical practice we have observed several AT/RT-like tumors, that fulfilled histopathological and all other biomarker criteria for a diagnosis of AT/RT, yet retained INI1 immunoreactivity. Recent studies have also reported preserved INI1 immunoreactivity among certain diagnosed AT/RTs. It is therefore necessary to re-evaluate INI1(+), AT/RT-like cases.MethodSanger sequencing, array CGH and mRNA microarray analyses were performed on PEBT samples to investigate their genomic landscapes.ResultsPatients with AT/RT and those with INI(+) AT/RT-like tumors showed a similar survival rate, and global array CGH analysis and INI1 gene sequencing showed no differential chromosomal aberration markers between INI1(-) AT/RT and INI(+) AT/RT-like cases. We did not misdiagnose MBs or PNETs as AT/RT-like tumors because transcriptome profiling revealed that not only did AT/RT and INI(+) AT/RT-like cases express distinct mRNA and microRNA profiles, their gene expression patterns were different from those of MBs and PNETs. The most similar transcriptome profile to that of AT/RTs was the profile of embryonic stem cells. However; the transcriptome profile of INI1(+) AT/RT-like tumors was more similar to that of somatic neural stem cells, while the profile of MBs was closer to that of fetal brain tissue. Novel biomarkers were identified that can be used to distinguish INI1(-) AT/RTs, INI1(+) AT/RT-like cases and MBs.ConclusionOur studies revealed a novel INI1(+) ATRT-like subtype among Taiwanese pediatric patients. New diagnostic biomarkers, as well as new therapeutic tactics, can be developed according to the transcriptome data that were unveiled in this work.

Dataset Information

Clinical outcome in pediatric glial and embryonal brain tumors correlates with in vitro multi-passageable neurosphere formation.

Publications

Clinical outcome in pediatric glial and embryonal brain tumors correlates with in vitro multi-passageable neurosphere formation.

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets