Abstract 2870: Optical imaging of bombesin and transferrin receptor expression are as effective as 18FDG in assessing drug efficacy
Authors: Tseng Jen-Chieh , Peterson Jeffrey D. 
Published: July 2017

Physical measurement of tumor volume reduction is the most commonly used method used to assess tumor progression and treatment efficacy in mouse tumor xenograft models, but the detection of tumor size changes can require repeated drug dosing and tumor measurements for several weeks. However, 18F-FDG PET imaging of altered glucose metabolism can be a more sensitive tool for early cancer detection/diagnosis as well as treatment assessment; cancer cells are known to have abnormally increased cellular metabolism that can be inhibited by drug treatment. To illustrate this, we used HCT-116 human colorectal tumor xenografts in nu/nu mice with sorafenib treatment, a clinically approved tyrosine protein kinase inhibitor (5 d treatment, 40 mg/kg). Treatment is known to inhibit PDGFR and VEGFR, as well as Raf kinases that regulate energy metabolism in tumors. Sofie G8 PET imaging of treated mice using 18F-FDG revealed a significant drop in tumor metabolism with as little as 2-3 days of treatment, a time in which there is typically little or no effect on tumor size. This approach was relatively low through-put, and required special procedures to accommodate use of radioactivity, but offered the option of daily imaging of tumor status. We also explored alternative optical imaging approaches that could offer higher through-put imaging as well as the potential for multiplex imaging. There is no fluorescent equivalent of 18F-FDG, so we focused on bombesin- and transferrin-receptors as potentially useful biomarkers for drug-induced inhibition in tumor metabolism. Bombesin receptors are upregulated in a variety of tumors and are important in energy metabolism and tumor growth. The rapid recycling kinetics also make this receptor highly sensitive to cellular metabolic changes. Transferrin receptors are also upregulated in most tumors and provide critical iron transport function vital for their increased enzymatic, proliferative, and metabolic requirements. We used targeted near infrared (NIR) fluorescent imaging probes, BombesinRSense™ 680 (BRS-680) and Transferrin-Vivo™ 750 (TfV-750), to monitor changes in receptor expression in HCT-116 tumor xenografts during the course of sorafenib treatment. Interestingly, both BR-680 and TfV-750 FLI on the IVIS® SpectrumCT yielded data quite similar to our results using 18F-FDG PET; reduction in these probes can be measured as early as 48-72 hours, in the absence of significant reduction of tumor size/viability. As expected, both PET and FLI were also highly effective at imaging sorafenib effects 7-8 days later (3-4 days following a 5-day sorafenib treatment regimen), with datasets in good agreement with physical measurement of changes in tumor size. These results suggest that BRS-680 and TfV-750 can serve as fluorescent surrogates for 18F-FDG PET both in measuring early metabolic changes and ultimate therapeutic outcomes following cancer treatment.

Citation Format: Jen-Chieh Tseng, Jeffrey D. Peterson. Optical imaging of bombesin and transferrin receptor expression are as effective as 18FDG in assessing drug efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2870. doi:10.1158/1538-7445.AM2017-2870