Glutamate-weighted chemical exchange saturation transfer magnetic resonance imaging (GluCEST MRI) detects glutaminase inhibition in a mouse model of triple-negative breast cancer

Glutamate is an important metabolite of glutaminolysis, a metabolic pathway employed by many aggressive cancers including triple-negative breast cancer. With the exception of the brain, in vivo detection of glutamate using 1H magnetic resonance spectroscopy (MRS) is challenging in tissues. Compared to MRS, glutamate chemical exchange saturation transfer MR imaging (GluCEST MRI) offers a more sensitive detection mechanism that is free of glutamine interference. Here we developed a robust, highly repeatable GluCEST MRI protocol in mice bearing human triple-negative breast cancer xenografts and treated with the potent glutaminase inhibitor CB-839. In paired studies, treatment with CB-839 for 2 days reduced the GluCEST asymmetry value compared to baseline (P < 0.05, n=10). The absolute change of the GluCEST asymmetry value was -2.5 percent points after CB-839 treatment versus +0.3 after vehicle (P < 0.01). Correspondingly, treatment with CB-839 reduced tumor glutamate concentrations by 1.5 mM, consistent with prior calibration between changes of the GluCEST value versus tissue glutamate concentration; CB-839, however, did not change tumor intracellular pH. These results demonstrate in a mouse model of TNBC the clinical utility of GluCEST MRI as a means to detect the early response to glutaminase inhibition.

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