HG-98IDENTIFICATION OF THE PRE-MALIGNANT CELL OF ORIGIN IN PEDIATRIC GLIOBLASTOMA MULTIFORME

Pediatric glioblastoma multiforme is an uncommon and highly mortal brain cancer. New therapeutic treatments are being intensively investigated by researchers in order to extend the survival of patients. The immune checkpoint inhibitor nivolumab in the treatment of pediatric glioblastoma multiforme is currently under review; it is a human immunoglobulin G4 monoclonal antibody that works against the programmed cell death protein 1 receptor, designed to enhance an immunologic reaction against cancer cells. Herein, we describe the first report of a bilateral optic neuritis induced by nivolumab in a grade 4 glioblastoma multiforme patient.

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Expression of p53, EGFR, pRb and bcl-2 Proteins in Pediatric Glioblastoma Multiforme: A Study of 54 Patients

Pediatric Neurosurgery ◽

10.1159/000088731 ◽

2005 ◽

Vol 41 (6) ◽

pp. 292-299 ◽

Cited By ~ 49

Author(s):

P.M. Ganigi ◽

V. Santosh ◽

B. Anandh ◽

B.A. Chandramouli ◽

V.R. Sastry Kolluri

Keyword(s):

Glioblastoma Multiforme ◽

Pediatric Glioblastoma

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HGG-04. ZINC ENHANCES TEMOZOLOMIDE CYTOTOXICITY IN PEDIATRIC GLIOBLASTOMA MULTIFORME MODEL SYSTEM

Neuro-Oncology ◽

10.1093/neuonc/noaa222.295 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii344-iii345

Author(s):

Amos Toren ◽

Michal Yalon ◽

Aner Dafni ◽

Ruty Mehrian-Shai

Keyword(s):

Glioblastoma Multiforme ◽

Combined Treatment ◽

Model System ◽

Growth Fraction ◽

Mutant P53 ◽

Viability Analysis ◽

Number Of Patients ◽

Pediatric Glioblastoma

Abstract BACKGROUND Temozolomide (TMZ) is an alkylating agent that has become the mainstay treatment of the most malignant brain cancer, glioblastoma multiforme (GBM). Unfortunately only a limited number of patients respond to it positively. We have shown that zinc metal reestablishes chemosensitivity in adult GBM in vitro and also in vivo but this effect has not been tested with pediatric GBM. METHODS Using Human pediatric glioblastoma cell lines- KNS42 (mutant p53/ MGMT [+]) and SF188 (mutant p53/ MGMT [-]), we investigated whether addition of zinc to TMZ enhances its cytotoxicity against GBM. RESULTS In vitro cell viability analysis showed that the cytotoxic activity of TMZ was substantially increased with addition of zinc and this response was accompanied by an elevation of p21, PUMA, BAX and a decrease in growth fraction as manifested by low ki67. Beta gal analysis showed that most of the remaining cells after the combination therapy are in senescence state. In order to eliminate the senescent population created as a result of the combined treatment of TMZ and Zinc, we decided to use a senolytic agent Navitoclax (ABT-263) that was demonstrated to be effective in reducing senescent cells by specific inhibition of Bcl-2, Bcl-XL and Bcl-w. Following the addition of Navitoclax to the combined treatment, SF188 cells, but not KNS42, show a significance reduction in viability compare to the combination treatment. CONCLUSIONS Our results suggest that zinc may serve as a potentiator of TMZ therapy in pediatric GBM patients and using a second hit with senolytic drug in some cases may be even more beneficial.

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TMOD-06. MODELLING ADULT AND PAEDIATRIC GLIOBLASTOMA MULTIFORME (GBM) USING A GENE SCREEN-BASED APPROACH IN MICE AND HUMAN IPSC-DERIVED CEREBRAL ORGANOIDS

Neuro-Oncology ◽

10.1093/neuonc/noz175.1105 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi263-vi263

Author(s):

Francesco Antonica ◽

Francesca Garilli ◽

Maria Del Mar Gardeazabal Bataller ◽

Lucia Santomaso ◽

Luca Tiberi

Keyword(s):

Glioblastoma Multiforme ◽

High Grade Glioma ◽

Tumour Marker ◽

Intratumor Heterogeneity ◽

Cell Of Origin ◽

Loss Of Function ◽

Newborn Mice ◽

Complex Process ◽

Adults And Children ◽

Human Ipsc

Abstract Glioblastoma multiforme (GBM) represent the most devastating form of high-grade glioma (HGG) affecting adults and children. Despite a multi-therapeutic approach consisting in surgery, radio- and chemo-therapy the prognosis remains poor. Several models such as xenograft, animal models and recently organoids, have been developed in order to investigate the physiopathology of GBM. Although several mouse models (where either gain- or loss-of function of genes/pathway found altered in patients induce tumour formation) have been generated many aspects of how the tumour is formed, evolves, infiltrates and recurs after treatments remain unclear. Another challenge is the creation of proper GBM models showing intratumor heterogeneity found in the patient tumour but missing in the animal model generated so far. To overcome the lack of that human tumour characteristic, we decided to generate new model of GBM using a gene screen-based approach in mice. Firstly, we analysed the genes found amplified or mutated in GBM patients; secondly, we over-expressed the candidate genes (combination of multiple genes found to be mutated or amplified in specific GBM patients) in the subventricular zone (SVZ) of P2 mouse brain. Thirdly, we analysed the formation of tumour after 2 months. We over-expressed roughly 50 combinations in newborn mice and found that only 3 successfully led to the formation of lesions positive for proliferation and brain tumour marker (i.e. GFAP). We are currently characterising the tumours by DNA methylation analysis and RNA-seq (for further confirmation of the cancer subtype and intratumor heterogeneity) or investigating the cell of origin of the tumour. Moreover, we are testing the tumorigenicity of specific in GBM-amplified/mutated gene combinations in hiPSC-derived cerebal organoids. Our data suggest that a gene screen-based approach can be used for quickly and easily assaying the tumorigenicity of genes found amplified/mutated in GBM patients as well as the biology behind such complex process.

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