Gliobastoma multiforme (GBM) is an aggressive malignant form of brain tumour for which effective therapies are limited. Genetically engineered mouse models (GEMMs) harbouring mutations in components of the main signalling pathways that are altered in human GBM – including the receptor tyrosine kinase (RTK)–RAS– phosphoinositide-3-kinase (PI3K) pathway – are available. However, these GEMMs display a long latency to tumorigenesis and advanced tumour heterogeneity, which represents a challenge in preclinical drug testing. In this study, Zoë Weaver Ohler and colleagues developed an orthotopic and tractable mouse model of GBM by transplanting brain tumour cells derived from GBM-GEMMs into the brain (orthotopically) of syngeneic mice (non-transgenic wild-type mice with identical genetic backgrounds and intact immune systems). This model develops GBM with features of the human disease, including high vascularisation and aggressive invasion of surrounding tissues, and thus was used to test the effects of two drugs that are currently in clinical trials for GBM and other solid tumours, namely BKM120 and PD0325901 [inhibitors of PI3K and mitogen-activated protein kinase (MAPK), respectively]. When tested in vitro and in vivo as single agents, neither drug improved mouse survival. However, combination therapy increased cancer cell apoptosis, decreased tumour cell proliferation and enhanced survival, owing to a synergistic effect of the drugs on suppression of the PI3K pathway (which regulates cell proliferation and survival). Therefore, this model represents a valuable preclinical system for advancing current therapies and for testing novel drugs and drug combinations against GBM. Page 45
A preclinical model of glioblastoma
A preclinical model of glioblastoma. Dis Model Mech 1 January 2015; 8 (1): e0102. doi:
Download citation file:
Advertisement
Cited by
Sex matters in preclinical research
DMM calls for improved inclusion, analysis and reporting of sex as a biological variable in preclinical animal modelling research. Read the full Editorial by Monica J. Justice.
Subject collection: Building advocacy into research
DMM’s new series - Building advocacy into research - features interviews, ‘The Patient’s Voice’, with patients and advocates for a range of disease types, with the aim of supporting the highest quality research for the benefit of all patients affected by disease.
Travelling Fellowships for early-career researchers
DMM and its sister journals offer Travelling Fellowships of up to £3,000 to graduate students and post-doctoral researchers wishing to make collaborative visits to other laboratories. Find out more about our Travelling Fellowships and read stories from previous grant recipients.
Read & Publish Open Access publishing: what authors say
We have had great feedback from authors who have benefitted from our Read & Publish agreement with their institution and have been able to publish Open Access with us without paying an APC. Read what they had to say.
The Forest of Biologists
Our Publisher Claire Moulton recently visited the two Woodland Trust UK sites where we are planting new native trees for published Research and Review papers and protecting ancient woodland on behalf of our peer reviewers.
Other journals from
The Company of Biologists