Abstract 5124: Molecular imaging of tumor energy metabolism as an early indicator of anticancer drug efficacy in small animal models
Authors: Jen-Chieh Tseng, Jeffrey Peterson
Journal: Cancer Research (2015)

Abstract Targeted cancer therapy aims to block key signaling pathways that are critical for tumor cell growth and survival. The blockage eventually results in cell death via apoptosis and eventual tumor growth suppression. This strategy has proven to be safe and efficacious, and the FDA has approved several targeted therapeutics in the past decade. Encouraged by the success in clinical development, many academic and pharmaceutical researchers are in active pursuit for the improvement of next generation targeted anti-cancer drugs. As a result, many new chemical and biological entities are emerging from initial screening of in vitro, in vitro and/or in silico selection processes. From the perspective of drug development, it poses a great challenge on the next stage of in vivo validation and demands a robust, accurate, and efficient method for assessment of these candidates in living animal models. Cancer cells are known to have abnormally increased cellular metabolism, and in the early stages of effective drug treatment, cancer cells show decreased metabolism and proliferation. These events occur prior to overt signs of cell destruction. Bioluminescence imaging technology can be used to detect changes in tumor viability in response to targeted therapy when using luciferase-expressing tumor cell lines. However, with many therapeutic treatments, particularly high-dose treatments, these early changes in tumor viability cannot be seen by bioluminescence imaging. We applied non-invasive near infrared (NIR) fluorescence imaging to address this challenge, using PerkinElmer's imaging agents; highly metabolic cancer cells have accompanying elevations in receptors for bombesin and transferrin on their surface that can be readily imaged using our fluorescent bombesin- and transferrin-targeted imaging agents (BombesinRSense 680 [BR680] and Transferrin-Vivo 750 [TV750]). In this report, we demonstrate the synergistic use of fluorescence (FLI) and bioluminescence imaging (BLI) to profile tumor metabolism and vitality, respectively, in response to a targeted anti-cancer drug, sorafenib. Sorafenib is a clinical approved tyrosine kinase inhibitor effectively blocking VEGFR, PDGFR and Raf signaling in cancer. At a higher daily dose of 110 mg/kg, the drug effective decrease viability of HCT116-luc human colon xenograft tumors within 48 hours, coinciding with the loss of both BR680 and TV750 fluorescent signals in tumor. Interestingly, at a lower dose of 40 mg/kg, BR680 signal reduction can still be observed early within 48 hours, but no significant reduction of tumor viability was observed until a week later. These results suggest the potential use of metabolic fluorescent imaging agents as robust, efficient and early biomarkers for pre-clinical development of targeted cancer drugs. Citation Format: Jen-Chieh Tseng, Jeffrey Peterson. Molecular imaging of tumor energy metabolism as an early indicator of anticancer drug efficacy in small animal models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5124. doi:10.1158/1538-7445.AM2015-5124