Hyperpolarized [1-C-13]Pyruvate Magnetic Resonance Spectroscopic Imaging for Evaluation of Early Response to Tyrosine Kinase Inhibition Therapy in Gastric Cancer

Purpose: To evaluate the use of hyperpolarized [1-C-13]pyruvate magnetic resonance spectroscopic imaging (HP-C-13 MRSI) for quantitative measurement of early changes in glycolytic metabolism and its ability to predict response to pan-tyrosine kinase inhibitor (Pan-TKI) therapy in gastric cancer (GCa). Procedures: Pan-TKI afatinib-sensitive NCI-N87 and resistant SNU16 human GCa cells were assessed for GLUT1, hexokinase-II (HKII), lactate dehydrogenase (LDHA), phosphorylated AKT (pAKT), and phosphorylated MAPK (pMAPK) at 0-72 h of treatment with 0.1 mu M afatinib. Subcutaneous NCI-N87 tumorbearing nude mice underwent [F-18]FDG PET/MRI and HP-C-13 MRSI at baseline and 4 days after treatment with afatinib 10 mg/kg/day or vehicle (n =10/group). Changes in PET and HP-C-13 MRSI metabolic parameters were compared between the two groups. Imaging findings were correlated with tumor growth and histopathology over 3 weeks of treatment. Results: In vitro analysis showed a continuous decrease in LDHA, pAKT, and pMAPK in NCI-N87 compared to SNU16 cells within 72 h of treatment with afatinib, without a significant change in GLUT1 and HKII in either cell type. [F-18]FDG PET of NCI-N87 tumors showed no significant change in PET measures at baseline and day 4 of treatment in either treatment group (SUVmean day 4/day 0: 2.7 +/- 0.42/2.34 +/- 0.38, p= 0.57 in the treated group vs. 1.73 +/- 0.66/2.24 +/- 0.43, p = 0.4 in the control group). HP-C-13 MRSI demonstrated significantly decreased lactate-to-pyruvate ratio (L/P) in treated tumors (L/P day 4/day 0: 0.83 +/- 0.30/1.10 +/- 0.20, p = 0.012 vs. 0.94 +/- 0.20/0.98 +/- 0.30, p = 0.75, in the treated vs. control group, respectively). Response to afatinib was confirmed with decreased tumor size over 3 weeks (11.10 +/- 16.50 vs. 293.00 +/- 79.30 mm(3), p < 0.001, treated group vs. control group, respectively) and histopathologic evaluation. Conclusions: HP-C-13 MRSI is a more representative biomarker of early metabolic changes in response to pan-TKI in GCa than [F-18]FDG PET and could be used for early prediction of of response to targeted therapies.