Hyperpolarized [1-¹³C]-Pyruvate Magnetic Resonance Spectroscopic Imaging of Prostate Cancer <i>In Vivo</i> Predicts Efficacy of Targeting the Warburg Effect.

Abstract

<b>Purpose:</b> To evaluate the potential of hyperpolarized [1-¹³C]-pyruvate magnetic resonance spectroscopic imaging (MRSI) of prostate cancer as a predictive biomarker for targeting the Warburg effect.<b>Experimental Design:</b> Two human prostate cancer cell lines (DU145 and PC3) were grown as xenografts. The conversion of pyruvate to lactate in xenografts was measured with hyperpolarized [1-¹³C]-pyruvate MRSI after systemic delivery of [1-¹³C] pyruvic acid. Steady-state metabolomic analysis of xenograft tumors was performed with mass spectrometry and steady-state lactate concentrations were measured with proton (¹H) MRS. Perfusion and oxygenation of xenografts were measured with electron paramagnetic resonance (EPR) imaging with OX063. Tumor growth was assessed after lactate dehydrogenase (LDH) inhibition with FX-11 (42 μg/mouse/day for 5 days × 2 weekly cycles). Lactate production, pyruvate uptake, extracellular acidification rates, and oxygen consumption of the prostate cancer cell lines were analyzed <i>in vitro</i> LDH activity was assessed in tumor homogenates.<b>Results:</b> DU145 tumors demonstrated an enhanced conversion of pyruvate to lactate with hyperpolarized [1-¹³C]-pyruvate MRSI compared with PC3 and a corresponding greater sensitivity to LDH inhibition. No difference was observed between PC3 and DU145 xenografts in steady-state measures of pyruvate fermentation, oxygenation, or perfusion. The two cell lines exhibited similar sensitivity to FX-11 <i>in vitro</i> LDH activity correlated to FX-11 sensitivity.<b>Conclusions:</b> Hyperpolarized [1-¹³C]-pyruvate MRSI of prostate cancer predicts efficacy of targeting the Warburg effect. <i>Clin Cancer Res; 24(13); 3137-48. ©2018 AACR</i>.