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A Multi-Parametric Imaging Investigation of the Response of C6 Glioma Xenografts to MLN0518 (Tandutinib) Treatment.

Boult, JK; Terkelsen, J; Walker-Samuel, S; Bradley, DP; Robinson, SP; (2013) A Multi-Parametric Imaging Investigation of the Response of C6 Glioma Xenografts to MLN0518 (Tandutinib) Treatment. PLoS One , 8 (4) e63024 - ?. 10.1371/journal.pone.0063024. Green open access

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Abstract

Angiogenesis, the development of new blood vessels, is essential for tumour growth; this process is stimulated by the secretion of numerous growth factors including platelet derived growth factor (PDGF). PDGF signalling, through its receptor platelet derived growth factor receptor (PDGFR), is involved in vessel maturation, stimulation of angiogenesis and upregulation of other angiogenic factors, including vascular endothelial growth factor (VEGF). PDGFR is a promising target for anti-cancer therapy because it is expressed on both tumour cells and stromal cells associated with the vasculature. MLN0518 (tandutinib) is a potent inhibitor of type III receptor tyrosine kinases that demonstrates activity against PDGFRα/β, FLT3 and c-KIT. In this study a multi-parametric MRI and histopathological approach was used to interrogate changes in vascular haemodynamics, structural response and hypoxia in C6 glioma xenografts in response to treatment with MLN0518. The doubling time of tumours in mice treated with MLN0518 was significantly longer than tumours in vehicle treated mice. The perfused vessel area, number of alpha smooth muscle actin positive vessels and hypoxic area in MLN0518 treated tumours were also significantly lower after 10 days treatment. These changes were not accompanied by alterations in vessel calibre or fractional blood volume as assessed using susceptibility contrast MRI. Histological assessment of vessel size and total perfused area did not demonstrate any change with treatment. Intrinsic susceptibility MRI did not reveal any difference in baseline R2* or carbogen-induced change in R2*. Dynamic contrast-enhanced MRI revealed anti-vascular effects of MLN0518 following 3 days treatment. Hypoxia confers chemo- and radio-resistance, and alongside PDGF, is implicated in evasive resistance to agents targeted against VEGF signalling. PDGFR antagonists may improve potency and efficacy of other therapeutics in combination. This study highlights the challenges of identifying appropriate quantitative imaging response biomarkers in heterogeneous models, particularly considering the multifaceted roles of angiogenic growth factors.

Type: Article
Title: A Multi-Parametric Imaging Investigation of the Response of C6 Glioma Xenografts to MLN0518 (Tandutinib) Treatment.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0063024
Publisher version: http://dx.doi.org/10.1371/journal.pone.0063024
Language: English
Additional information: © 2013 Boult et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The authors acknowledge the support received for The Institute of Cancer Research CR-UK and EPSRC Cancer Imaging Centre in association with the MRC and Department of Health (England) (grant C1060/A10334) and NHS funding to the NIHR Biomedical Research Centre. SPR was the recipient of a Royal Society University Research Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Department of Imaging
URI: https://discovery.ucl.ac.uk/id/eprint/1393409
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