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[摘要]：No clinically validated biomarkers exist to image tumor responses to antiangiogenic therapy. Here, we report the utility of hyperpolarized C-13 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, C-13 flux between hyperpolarized [1-C-13] pyruvate and [1-C-13] lactate decreased after anti-VEGF therapy and correlated with reduced perfusion. Production of [1,4-C-13(2)] malate from hyperpolarized [1,4-C-13(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 C-13 flux from hyperpolarized [1-C-13] 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-C-13] 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-C-13(2)] malate from hyperpolarized [1,4-C-13(2)] fumarate in therapy-resistant tumors also increased. Together, our findings show that hyperpolarized C-13 MRS detects early responses to anti-VEGF therapy, including vascular normalization or vascular destruction and cell death. Cancer Res; 72(4); 854-64. (C) 2012 AACR. |
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