Abstract 4318: Biomarker evaluation during an image-guided intracranial murine glioma study of radiation and sunitinib
Authors: Chung Caroline , Foltz Warren , Wildgoose Petra , Burrell Kelly , Lindsay Patricia , Kallehauge Jesper , Camphausen Kevin , Kassner Andrea , Jaffray David , Menard Cynthia , Zadeh Gelareh 
Published: February 2011

Introduction: Tumour angiogenesis, a hallmark of glioblastoma multiforme, serves as a potential therapeutic target. Sunitinib (SU) is a multi-targeted tyrosine kinase inhibitor with antiantiogenic activity that may enhance radiation (RT) effects. In preclinical studies using intracranial (IC) mouse tumour models, a major challenge is the ability to evaluate IC tumour size, growth and vascular changes over time. This study aims to use an image-guided experimental design to evaluate the effects of RT and/or SU in an IC murine glioma model using serial micro-MRI and urine biomarkers with corresponding pathology, tumour growth delay (TGD) and survival (OS)outcomes.

Methods:

U87 glioma cells were inoculated by IC injection in the right frontal lobe of 58 NOD SCID mice. Imaging was performed on a 7-Tesla Bruker BioSpec on day 7 post-injection (treatment D0), D3, 7, 10, 14, 17 and 21. Mice with visible tumours on D0 T2-weighted (T2-w) imaging were stratified by tumour size to treatments: (1) control (CTRL) - placebo (2) RT - RT + placebo (3) SU - oral gavage SU (4) RT + SU. RT 8 Gy was delivered in 1 fraction to the right hemi-brain on D1 under image-guidance. SU 0.8 mg or placebo was administered by oral gavage. Serial imaging/analysis included: (1) T2-w imaging (2) Quantitative T1 (3) DCE-MRI - initial area under the DCE curve at 60 seconds (iAUC60) (4) diffusion weighted imaging - apparent diffusion coefficient (ADC) (5) contrast-enhanced T1-w imaging (T1-gad). Expression of angiogenesis markers were measured in serial urine samples. Pathological evaluation included tumour size, cell density, vessel density/permeability and apoptosis.

Results: Fifty-two mice with tumours were assigned to treatment arms such that mean tumour volume for each arm was 0.58 - 0.61mm3 (p&gt;0.05) on D0. No mice expired with serial contrast-enhanced imaging. OS was significantly better with RT (p=0.008) and SU+RT (p=0&lt;0.001) than CTRL, and SU+RT better than SU (p=0.018) and RT (p=0.05). Exponential tumour growth occurred in CTRLs but TGD was noted in all treatment arms until D14. Changes in iAUC60 showed trends/differences between treatment arms only at early timepoints: (1) RT - rise by D3 (2) SU - stable during SU (3) SU+RT - decrease of 30.1+6.8% by D3, maintained during SU. Baseline tumour ADC values were 8±5% above CL brain across all animals. Rise in ADC was greatest with RT and SU+RT (43±10%, 28±7%) than CTRL and SU (16±4%, 19±19%) at D10.

Conclusion: This study demonstrates the potential utility of image-guidance to augment murine intracranial tumour studies of RT and AA therapy. Survival was improved with combined SU+RT. Promising early biomarkers of response identified to date include DCE at D3, and ADC at D10, warranting further investigation in a larger cohort. Further study of these markers may improve temporal characterization of vessel normalization and enable studies to optimize scheduling of antiangiogenic therapies with radiation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4318.