Authors:
SE Bohndiek, MI Kettunen, D-E Hu, KM Brindle
Journal name: 
Cancer Res
Citation info: 
72(4):854-864
Abstract: 
No clinically validated biomarkers exist to image tumor responses to antiangiogenic therapy. Here, we report the utility of hyperpolarized (13)C magnetic resonance spectroscopy (MRS) to detect the early effects of anti-VEGF therapy. In two colorectal cancer xenograft models, displaying differential sensitivity to VEGF blockade, we compared hyperpolarized MRS with measurements of tumor perfusion using dynamic contrast agent-enhanced (DCE)-MRI and tumor cellularity using diffusion-weighted MRI of the apparent diffusion coefficient (ADC) of tissue water. In tumors sensitive to anti-VEGF therapy, (13)C flux between hyperpolarized [1-(13)C]pyruvate and [1-(13)C]lactate decreased after anti-VEGF therapy and correlated with reduced perfusion. Production of [1,4-(13)C(2)]malate from hyperpolarized [1,4-(13)C(2)]fumarate increased in parallel with tumor cell necrosis, preceding any change in tumor ADC. In contrast, tumors that were less sensitive to anti-VEGF therapy showed an increase in (13)C flux from hyperpolarized [1-(13)C]pyruvate and an increase in uptake of a gadolinium contrast agent, whereas tumor ADC decreased. Increased label flux could be explained by vascular normalization after VEGF blockade, increasing delivery of hyperpolarized [1-(13)C]pyruvate as observed. Despite the minimal response of these tumors to treatment, with only a minor increase in necrosis observed histologically, production of [1,4-(13)C(2)]malate from hyperpolarized [1,4-(13)C(2)]fumarate in therapy-resistant tumors also increased. Together, our findings show that hyperpolarized (13)C MRS detects early responses to anti-VEGF therapy, including vascular normalization or vascular destruction and cell death.
DOI: 
http://doi.org/10.1158/0008-5472.CAN-11-2795
Research group: 
Brindle Group, VISION Lab
E-pub date: 
15 Feb 2012