Abstract B257: Chronic dosing with MLN0518 (Tandutinib), a small molecule PDGFRα/β inhibitor, reduces tumor growth, hypoxia, and perfusion in C6 glioma xenografts: An investigation using immunohistochemical and MRI methods
Authors: Boult Jessica K.R. , Walker-Samuel Simon , Bradley Daniel P. , Robinson Simon P. 
Published: June 2012

Glioblastoma multiforme (GBM) is heavily reliant upon angiogenesis for growth and represents one of the most vascularised human tumors. MLN0518 (Tandutinib) is a type III receptor tyrosine kinase inhibitor (RTKi) with activity against PDGFRα/β, FLT3 and c-KIT in the submicromolar range, but exhibits no significant inhibition of a broad range of other kinases. MLN0518 is currently in phase II trials as monotherapy and in combination with Bevacizumab for recurrent glioblastoma.

In this study we aimed to investigate 1) vascular haemodynamic and structural response, and 2) hypoxic changes of C6 glioma xenografts to MLN0518 using immunohistochemical and MRI methods.

C6 rat glioma xenografts were grown subcutaneously in nude mice. When tumors reached 200±100mm3 they were stratified to receive either vehicle (5% dextrose, n=9) or 20mg/kg MLN0518 (n=9) subcutaneously BID for 10 days. At study end tumors were excised and the total endothelial cell concentration (CD31), degree of perfused vasculature (Hoechst 33342), and hypoxia (pimonidazole) were quantified by immunohistochemistry and fluorescence microscopy.

Tumors in mice treated with MLN0518 grew significantly slower than vehicle-treated tumors (volume doubling time 5.9±0.4 days compared with 4.6±0.2 days, p&lt;0.05).

There was no significant difference in either Hoechst 33342 perfused area or total endothelial cell area as assessed by CD31 staining. However, when the distribution of staining was analyzed it revealed that the percentage of the total vessels perfused at the time of Hoechst 33342 injection was 25.4% lower in MLN0518 than vehicle-treated tumors (p&lt;0.05), and equated to a 37.7% reduction in an overall perfused vessel area in treated vs. control tumors (p&lt;0.05).

Finally, and most strikingly, despite having a lower perfused vessel area MLN0518-treated tumors were 28.0% less hypoxic than control tumors as assessed by pimonidazole adduct formation (p&lt;0.05).

The data demonstrate that chronic administration of MLN0518 limits the growth of C6 glioma xenografts and reduces both the mean perfused vessel fraction and hypoxic area. The co-registration of Hoechst 33342 and CD31 staining also highlights the limitation of solely using a pan-endothelial marker to assess vascular response.

To complement these growth and histological readouts we are currently exploring the use of susceptibility contrast enhanced magnetic resonance imaging to derive imaging biomarkers of tumor fractional blood volume (%) and vessel size index (µm).

Tumor hypoxia is well known to promote a more metastatic, malignant, angiogenic and chemo-/radio-resistant lesion. MLN0518 is one of few chronically dosed RTK inhibitors that reduce hypoxia in xenograft tumors. Thus, MLN0518 may prove effective for the treatment of well vascularised tumors such as GBM.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B257.