Glutamate-Weighted Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Detects Glutaminase Inhibition in a Mouse Model of Triple-Negative Breast Cancer.

Abstract

Glutamate is an important metabolite of glutaminolysis, a metabolic pathway used by many aggressive cancers, including triple-negative breast cancer (TNBC). With the exception of the brain, <i>in vivo</i> detection of glutamate in tissues using ¹H magnetic resonance spectroscopy (MRS) is challenging. Compared with MRS, glutamate-weighted 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 TNBC xenografts and treated with a potent glutaminase inhibitor, CB-839. In paired studies, treatment with CB-839 for 2 days reduced the GluCEST asymmetry value compared with baseline (<i>P</i> < 0.05, <i>n</i> = 10). The absolute change of the GluCEST asymmetry value was -2.5 percent points after CB-839 treatment versus +0.3 after vehicle (<i>P</i> < 0.01). Correspondingly, treatment with CB-839 reduced tumor glutamate concentrations by 1.5 mmol/L, 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 breast cancer the utility of GluCEST MRI to detect the early response to glutaminase inhibition.<b>Significance:</b> A sensitive method enables noninvasive detection of tumor response to inhibitors of glutamine metabolism. <i>Cancer Res; 78(19); 5521-6. ©2018 AACR</i>.