Leo Lee Tsai MD, PhD, Presenter: Co-founder, Agile Devices Inc Stockholder, Agile Devices Inc Research Consultant, Agile Devices Inc

Xiaoen Wang MD, Abstract Co-Author: Nothing to Disclose

Gopal Varma PhD, Abstract Co-Author: Nothing to Disclose

Rupal Bhatt, Abstract Co-Author: Nothing to Disclose

David C. Alsop PhD, Abstract Co-Author: Research support, General Electric Company Royalties, General Electric Company

Aaron Keith Grant PhD, Abstract Co-Author: Nothing to Disclose

Renal cell carcinomas (RCC) demonstrate high rates of glycolysis, associated with high expression of the glucose transporter GLUT1, which is in turn regulated by hypoxia-induced factors (HIF). Here we use hyperpolarized 13-C pyruvate (h13C-pyruvate) to provide in vivo monitoring of glycolysis and perfusion in a renal cell carcinoma (RCC) xenograft mouse model treated with sunitinib, and to correlate with GLUT1 and CD34 expression.

Four mice were implanted with A498 VHL-deficient RCC. Two were treated with sunitinib, and two controls were administered phosphate-buffered saline (PBS). One sunitinib-treated mice was imaged 7 days after treatment initiation, the other 32-days post-treatment, at resistance. Control mice were imaged pre-PBS and 6-7 days following PBS. Tumors were harvested after final images for immunohistological analysis. MRI was performed at 9.4 T using: (1) Proton-T2-weighed rapid acquisition with refocused echoes (RARE) sequence for anatomical localization, (2) h13C-pyruvate imaging with echo-planar spectroscopic imaging (EPSI), and (3) arterial-spin-label (ASL) perfusion mapping with flow-sensitive inversion-recovery.

Control tumors treated with PBS show high uptake of C13-pyruvate and conversion into lactate (Figure 1a- proton image, 1b- lactate image overlay). Sunitnib-treated tumor at 7d demonstrated decreased perfusion on ASL corresponding to decreased C13-pyruvate uptake, and altered lactate levels at both response and resistance. High GLUT1 expression was sustained during growth, treatment, and at resistance, while CD-34 expression was reduced during sunitinib response, and restored at resistance, as demonstrated in Figures 2a-2c (GLUT1-red, CD34-green, Hoechst nuclei staining-blue).

Glycolytic metabolism is altered during RCC response to sunitinib and subsequent resistance, though overall activity is sustained, as demonstrated by persistent GLUT1 expression. C13-pyruvate uptake correlates with perfusion as measured by ASL and CD34 expression.

h13C-pyruvate MRI provides vivo assessment of glycolytic activity and perfusion within an RCC model, correlating to treatment response and resistance. This method has translational potential for clinical tumor monitoring in patients.

Tsai, L, Wang, X, Varma, G, Bhatt, R, Alsop, D, Grant, A, Characterization of Glycolytic Activity and Perfusion in a Renal Cell Carcinoma Mouse Model during Sunitinib Response and Resistance with Hyperpolarized 13-C-pyruvate MRI.  Radiological Society of North America 2014 Scientific Assembly and Annual Meeting, - ,Chicago IL. http://archive.rsna.org/2014/14009663.html