Abstract LB-48: Non-invasive imaging of response to MEK Inhibition with AZD6244 (ARRY-142886) in a human melanoma xenograft monitored by diffusion-weighted MRI

Abstract

Abstract Background: Non-invasive imaging biomarkers are key to the development and evaluation of novel targeted anti-cancer drugs. The MEK inhibitor, AZD6244 (ARRY-142886), is one such agent that is now undergoing clinical testing. This drug causes inhibition of growth and induction of apoptosis in a range of pre-clinical tumor models. We therefore reasoned that such effects could translate to changes in tumor tissue cellular density that may be detectable by diffusion-weighted magnetic resonance imaging (DW-MRI). Here we test this hypothesis in a human melanoma xenograft model. Methodology: Female nude mice bearing V600E BRAF WM266.4 melanoma sub-cutaneous xenografts (∼550 mm3 volume) were treated twice daily for 3 days by gavage with vehicle (n=9) or 75mg/kg AZD6244 (n=9). DW-MRI data were acquired pre- and 3h post the last dose, and correlated with phosphorylated (P-) ERK1/2 and the necrotic tumor fraction by histological analysis of excised tumors. Results: Our results show that AZD6244-treated tumors were not significantly different in size compared to day 0 (100±6%) while the vehicle treated-tumors had grown by ∼ 1.4-fold (p=0.001). Relative to day 0, the mean values of the apparent diffusion coefficient (ADC), a parameter that is inversely related to tissue cellularity, were not changed in the control group (109±12%, p=0.45) but increased significantly to 160±20% (p=0.01) in the AZD6244-treated group. This effect correlated with substantially reduced P-ERK1/2 levels and increased tumor necrosis from 10± 10% in the vehicle group to 60±9% in the drug-treated group (p=0.036). Conclusions: This study highlights changes in ADC that follow treatment with a MEK signaling inhibitor, and which precede tumor shrinkage. Our data support the use of ADC as a non-invasive pharmacodynamic biomarker for early assessment of response to AZD6244 and other therapies targeted at MEK-ERK1/2 signaling during clinical trials. Acknowledgements: This work was funded by Cancer Research UK [CUK] project grant C1060/A6916, AstraZeneca and The Royal Society. We acknowledge the support received from the CRUK and EPSRC Cancer Imaging Centre in association with the MRC and Department of Health (England) grant C1060/A10334, also NHS funding to the NIHR Biomedical Research Centre. 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 LB-48.