Abstract 107: Lipid metabolism inhibitors enhance glycolysis and FDG-PET imaging of prostate cancer tumors

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Introduction: Positron Emission Tomography (PET) with18F-deoxyglucose (FDG) has gained a major role in the clinical setting for detection, staging and assessment of treatment response for a number of epithelial cancers. However, staging of primary or metastatic prostate cancer with 18F-FDG-PET is suboptimal, likely due to the low glucose uptake and enhanced lipid metabolism characteristic of primary prostate tumors. The exact mechanisms of aerobic glycolysis (Warburg effect) and lipid metabolism in prostate cancer (PCa) cells remain unknown. However, 18F-FDG-PET imaging of metastatic PCa might be enhanced by altering the intrinsic energy metabolism of involved sites. Experimental Procedures: In vitro radioactive studies were carried out to confirm the specificity of etomoxir for blocking lipid oxidation and enhancing glucose uptake at 24 hours in prostate cancer cell lines. For in vivo studies, three mouse models of PCa were used: Male nude mice with subcutaneous xenograts or orthotopic injections and TRAMP mice that develop prostate cancer with age. All mice were treated with a single dose of the lipid oxidation inhibitor etomoxir (20 mg/kg) or vehicle (saline) for 24 hours. A basal FDG-PET scan was performed before the drug treatment, followed by a second FDG-PET scan after 24 hours. Western blot analysis was used to validate the molecular mechanisms of increased FDG uptake. Results: The clinically safe drug etomoxir blocks fat oxidation within 4 hours and increases glucose uptake in cultured PCa cells. Subcutaneous xenografts showed a significant increase in normalized FDG uptake (NUV) after a single dose of etomoxir compared to basal NUV (1.4 fold change, p =0.03). This enhancing effect was not seen in mice treated with saline (vehicle). Mice with orthotopic xenografts and 20-week old TRAMP mice showed a 2.7-fold (p=0.03) and 1.6-fold (p=0.07) increase in FDG uptake, respectively, over basal. Protein examination of the excised subcutaneous tumors showed increased hexokinase-II content and activated mTOR and p70-S6 Kinase proteins in the etomoxir-treated tumors when compared to saline-treated tumors. Conclusion: 18F-FDG is a commercially available tracer that is widely used for standard-of-care and research-based oncologic imaging. Blocking lipid oxidation in PCa tumors has the potential to improve diagnostic imaging, since 18F-FDG that accumulates inside the cell can enhance FDG-PET imaging of prostate cancer tumors to detectable and quantifiable levels. Citation Format: Isabel R. Schlaepfer, Colton T. Pac, Natalie J. Serkova, Gagan Deep, Rajesh Agarwal, Scott D. Cramer, Robert H. Eckel, L. Michael Glode. Lipid metabolism inhibitors enhance glycolysis and FDG-PET imaging of prostate cancer tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 107. doi:10.1158/1538-7445.AM2014-107