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J Neurooncol. 2018 Nov 16. doi: 10.1007/s11060-018-03038-2. [Epub ahead of print]

International experience in the development of patient-derived xenograft models of diffuse intrinsic pontine glioma.

Author information

1
Children's Cancer Institute, Randwick, NSW, 2031, Australia.
2
Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, London, UK.
3
Department of Pediatric Oncology, VU University Medical Center, Amsterdam, the Netherlands.
4
Unite Mixte de Recherche 8203 du Centre National de la Recherche Scientifique (CNRS) et Departement de Cancerologie de l'Enfant et de l'Adolescent, Gustave Roussy et Universite Paris-Saclay, Villejuif, France.
5
Brain Tumor Center, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, USA.
6
Histopathology Department, Beaumont Hospital, Dublin, Ireland.
7
Department of Neurosurgery, Temple Street Children's University Hospital, Dublin, Ireland.
8
Our Lady's Children's Hospital, Dublin, Ireland.
9
Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, 2052, Australia.
10
Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC, 3052, Australia.
11
Neurosurgery Unit, Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children's Hospital, Rome, Italy.
12
Neuro-Oncology Unit, Department of Hemato-Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, Rome, Italy.
13
Department of Oncology, Princess Margaret Hospital, Perth, WA, Australia.
14
Lady Cilento Children's Hospital, Brisbane, Australia.
15
Department of Haematology-Oncology, Women's and Children's Hospital, Adelaide, SA, Australia.
16
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
17
Stanford University and Lucile Packard Children's Hospital, Palo Alto, CA, USA.
18
Children's Cancer Institute, Randwick, NSW, 2031, Australia. d.ziegler@unsw.edu.au.
19
Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, 2052, Australia. d.ziegler@unsw.edu.au.

Abstract

PURPOSE:

Diffuse intrinsic pontine glioma is the most aggressive form of high grade glioma in children with no effective therapies. There have been no improvements in survival in part due poor understanding of underlying biology, and lack of representative in vitro and in vivo models. Recently, it has been found feasible to use both biopsy and autopsy tumors to generate cultures and xenograft models.

METHODS:

To further model development, we evaluated the collective international experience from 8 collaborating centers to develop DIPG pre-clinical models from patient-derived autopsies and biopsies. Univariate and multivariate analysis was performed to determine key factors associated with the success of in vitro and in vivo PDX development.

RESULTS:

In vitro cultures were successfully established from 57% of samples (84.2% of biopsies and 38.2% of autopsies). Samples transferred in DMEM media were more likely to establish successful culture than those transported in Hibernate A. In vitro cultures were more successful from biopsies (84.2%) compared with autopsies (38.2%) and as monolayer on laminin-coated plates than as neurospheres. Primary cultures successfully established from autopsy samples were more likely to engraft in animal models than cultures established from biopsies (86.7% vs. 47.4%). Collectively, tumor engraftment was more successful when DIPG samples were directly implanted in mice (68%), rather than after culturing (40.7%).

CONCLUSION:

This multi-center study provides valuable information on the success rate of establishing patient-derived pre-clinical models of DIPG. The results can lead to further optimization of DIPG model development and ultimately assist in the investigation of new therapies for this aggressive pediatric brain tumor.

KEYWORDS:

Brainstem glioma; DIPG; H3K27M; Neurospheres; PDX; Patient-derived xenografts

PMID:
30446898
DOI:
10.1007/s11060-018-03038-2

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