Abstract
Physical measurement of tumor volume reduction is the most commonly used approach to assess tumor progression and treatment efficacy in mouse tumor models. However, it is relatively insensitive, and often requires long treatment courses to achieve gross physical tumor destruction. As alternatives, several non-invasive imaging methods such as bioluminescence imaging (BLI), fluorescence imaging (FLI) and positron emission tomography (PET) have been developed for more accurate measurement. As tumors have elevated glucose metabolism, 18F-fludeoxyglucose (18F-FDG) has become a sensitive PET imaging tracer for cancer detection, diagnosis, and efficacy assessment by measuring alterations in glucose metabolism. In particular, the ability of 18F-FDG imaging to detect drug-induced effects on tumor metabolism at a very early phase has dramatically improved the speed of decision-making regarding treatment efficacy. Here we demonstrated an approach with FLI that offers not only comparable performance to PET imaging, but also provides additional benefits, including ease of use, imaging throughput, probe stability, and the potential for multiplex imaging. In this report, we used sorafenib, a tyrosine kinase inhibitor clinically approved for cancer therapy, for treatment of a mouse tumor xenograft model. The drug is known to block several key signaling pathways involved in tumor metabolism. We first identified an appropriate sorafenib dose, 40 mg/kg (daily on days 0–4 and 7–10), that retained ultimate therapeutic efficacy yet provided a 2–3 day window post-treatment for imaging early, subtle metabolic changes prior to gross tumor regression. We then used 18F-FDG PET as the gold standard for assessing the effects of sorafenib treatment on tumor metabolism and compared this to results obtained by measurement of tumor size, tumor BLI, and tumor FLI changes. PET imaging showed ~55–60% inhibition of tumor uptake of 18F-FDG as early as days 2 and 3 post-treatment, without noticeable changes in tumor size. For comparison, two FLI probes, BombesinRSense™ 680 (BRS-680) and Transferrin-Vivo™ 750 (TfV-750), were assessed for their potential in metabolic imaging. Metabolically active cancer cells are known to have elevated bombesin and transferrin receptor levels on the surface. In excellent agreement with PET imaging, the BRS-680 imaging showed 40% and 79% inhibition on days 2 and 3, respectively, and the TfV-750 imaging showed 65% inhibition on day 3. In both cases, no significant reduction in tumor volume or BLI signal was observed during the first 3 days of treatment. These results suggest that metabolic FLI has potential preclinical application as an additional method for detecting drug-induced metabolic changes in tumors.
Highlights
Current preclinical evaluation of anti-cancer treatments using animal models relies predominantly on physical measurements of the reduction of tumor volume
We found that tumors from sorafenib-treated animals had significantly lower bioluminescence, BombesinRSenseTM 680 (BRS-680), and Transferrin-VivoTM 750 (TfV-750) signal as tumors regressed at this later stage of treatment (Fig 5)
Cancer cells typically acquire several mutations in pivotal pro-oncogenic signaling regulators in order to cope with their survival needs
Summary
Current preclinical evaluation of anti-cancer treatments using animal models relies predominantly on physical measurements of the reduction of tumor volume This is a relatively insensitive measure of anti-tumor effects, requiring repeated drug dosing and frequent measurements, often over multiple weeks. Researchers and clinicians since the late 1980’s [3] took advantage of the Warburg effect and developed a glucose analog 18F-fludeoxyglucose (18F-FDG) for PET imaging Since this imaging technology has become the gold standard imaging method for both tumor detection and efficacy assessment of anti-cancer therapies in clinic [4,5,6,7]. Targeting these important regulatory molecules should cause immediate metabolic decrease in tumor cells prior to eventual tumor volume regression, a complex and slow process involving both tumor cells and normal host cells
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