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.
Highlights
Tumour growth is dependent upon angiogenesis, the development of new blood vessels, to provide a nutritive blood supply [1]
platelet derived growth factor (PDGF)/platelet derived growth factor receptor (PDGFR) signalling is an attractive target for anti-cancer therapy; it has a pleiotropic role on the tumour microenvironment, principally in vascular maturation, but it has direct effects on tumour cells and hypoxia [4,7,8,25]
PDGFRa is highly expressed by tumour cells and PDGFRb is preferentially expressed by vascular endothelial and mural cells within tumours
Summary
Tumour growth is dependent upon angiogenesis, the development of new blood vessels, to provide a nutritive blood supply [1]. This process is stimulated by the secretion of numerous growth factors by tumour cells, endothelial cells and tumour associated macrophages [2]. Tumour vasculature is structurally irregular, with vessels being more tortuous, fragile, dilated and hyperpermeable in comparison to normal blood vessels [3] Considering their critical role in tumour development and progression, angiogenic growth factors are the target for many novel cancer therapeutics. A multi-parametric MRI and histopathological approach was used to interrogate the vascular structural and haemodynamic response, and the hypoxic changes in C6 glioma xenografts in response to MLN0518
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