Application of <i>in vivo</i> imaging techniques to monitor therapeutic efficiency of PLX4720 in an experimental model of microsatellite instable colorectal cancer

Abstract

// Sarah Rohde 1 , Tobias Lindner 2 , Stefan Polei 2 , Jan Stenzel 2 , Luise Borufka 1 , Sophie Achilles 1 , Eric Hartmann 1 , Falko Lange 3 , Claudia Maletzki 4 , Michael Linnebacher 4 , &Auml;nne Glass 5 , Sarah Marie Schwarzenb&ouml;ck 6 , Jens Kurth 6 , Alexander Hohn 6 , Brigitte Vollmar 7 , Bernd Joachim Krause 6 and Robert Jaster 1 1 Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock, Germany 2 Core Facility Multimodal Small Animal Imaging, Rostock University Medical Center, Rostock, Germany 3 Oscar-Langendorff-Institute of Physiology, Rostock University Medical Center, Rostock, Germany 4 Molecular Oncology and Immunotherapy, Department of General Surgery, Rostock University Medical Center, Rostock, Germany 5 Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany 6 Department of Nuclear Medicine, Rostock University Medical Center, Rostock, Germany 7 Institute of Experimental Surgery, Rostock University Medical Center, Rostock, Germany Correspondence to: Robert Jaster, email: robert.jaster@med.uni-rostock.de Keywords: colorectal cancer, mouse model, PLX4720, 5&rsquo;-fluorouracil, in vivo imaging Received: February 01, 2017&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: June 01, 2017&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: July 15, 2017 ABSTRACT Objectives: Patient-derived tumor cell lines are a powerful tool to analyze the sensitivity of individual tumors to specific therapies in mice. An essential prerequisite for such an approach are reliable quantitative techniques to monitor tumor progression in vivo . Methods: We have employed HROC24 cells, grown heterotopically in NMRI Foxn1 nu mice, as a model of microsatellite instable colorectal cancer to investigate the therapeutic efficiencies of 5&rsquo;-fluorouracil (5&rsquo;-FU) and the mutant BRAF inhibitor PLX4720, a vemurafenib analogue, by three independent methods: external measurement by caliper, magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) with 2-deoxy-2-( 18 F)fluoro-D-glucose ( 18 F-FDG). Results: Repeated measure ANOVA by a general linear model revealed that time-dependent changes of anatomic tumor volumes measured by MRI differed significantly from those of anatomic volumes assessed by caliper and metabolic volumes determined by PET/CT. Over the investigation period of three weeks, neither 5&rsquo;-FU, PLX4720 nor a combination of both drugs affected the tumor volumes. Also, there was no drug effect on the apparent diffusion constant (ADC) value as detected by MRI. Interestingly, however, PET/CT imaging showed that PLX4720-containing therapies transiently reduced the standardized uptake value (SUV), indicating a temporary response to treatment. Conclusions: 5&rsquo;-FU and PLX4720 were largely ineffective with respect to HROC24 tumor growth. Tumoral uptake of 18 F-FDG, as expressed by the SUV, proved as a sensitive indicator of small therapeutic effects. Metabolic imaging by 18 F-FDG PET/CT is a suitable approach to detect effects of tumor-directed therapies early and even in the absence of morphological changes.