Sonja Schelhaas1, Lydia Wachsmuth2, Sven Hermann1, Natascha Rieder3, Astrid Heller3, Kathrin Heinzmann4, Davina J Honess5, Donna-Michelle Smith5, Inga B Fricke1, Nathalie Just2, Sabrina Doblas6, Ralph Sinkus7, Christian Döring1, Klaus P Schäfers1, John R Griffiths5, Cornelius Faber2, Richard Schneider8, Eric O Aboagye4, Andreas H Jacobs9,10. 1. European Institute for Molecular Imaging, Westfälische Wilhelms-Universität Münster, Münster, Germany. 2. Department of Clinical Radiology, University Hospital of Münster, Münster, Germany. 3. Pathology and Tissue Analytics, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany. 4. Comprehensive Cancer Imaging Centre, Imperial College London, London, United Kingdom. 5. Cancer Research U.K. Cambridge Institute, Cambridge, United Kingdom. 6. Laboratory of Imaging Biomarkers, UMR 1149-CRI, INSERM, Paris Diderot University, Paris, France. 7. Imaging Sciences and Biomedical Engineering Division, Kings College, London, United Kingdom. 8. Merck KGaA, Darmstadt, Germany; and. 9. European Institute for Molecular Imaging, Westfälische Wilhelms-Universität Münster, Münster, Germany ahjacobs@uni-muenster.de. 10. Department of Geriatric Medicine, Johanniter Hospital, Bonn, Germany.
Abstract
Noninvasive monitoring of tumor therapy response helps in developing personalized treatment strategies. Here, we performed sequential PET and diffusion-weighted MRI to evaluate changes induced by a FOLFOX-like combination chemotherapy in colorectal cancer xenografts, to identify the cellular and molecular determinants of these imaging biomarkers. Methods: Tumor-bearing CD1 nude mice, engrafted with FOLFOX-sensitive Colo205 colorectal cancer xenografts, were treated with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) weekly. On days 1, 2, 6, 9, and 13 of therapy, tumors were assessed by in vivo imaging and ex vivo analyses. In addition, HCT116 xenografts, which did not respond to the FOLFOX treatment, were imaged on day 1 of therapy. Results: In Colo205 xenografts, FOLFOX induced a profound increase in uptake of the proliferation PET tracer 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) accompanied by increases in markers for proliferation (Ki-67, thymidine kinase 1) and for activated DNA damage response (γH2AX), whereas the effect on cell death was minimal. Because tracer uptake was unaltered in the HCT116 model, these changes appear to be specific for tumor response. Conclusion: We demonstrated that 18F-FLT PET can noninvasively monitor cancer treatment-induced molecular alterations, including thymidine metabolism and DNA damage response. The cellular or imaging changes may not, however, be directly related to therapy response as assessed by volumetric measurements.
Noninvasive monitoring of tumor therapy response helps in developing personalized treatment strategies. Here, we performed sequential PET and diffusion-weighted MRI to evaluate changes induced by a FOLFOX-like combination chemotherapy in colorectal cancer xenografts, to identify the cellular and molecular determinants of these imaging biomarkers. Methods:Tumor-bearing CD1nude mice, engrafted with FOLFOX-sensitive Colo205 colorectal cancer xenografts, were treated with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) weekly. On days 1, 2, 6, 9, and 13 of therapy, tumors were assessed by in vivo imaging and ex vivo analyses. In addition, HCT116 xenografts, which did not respond to the FOLFOX treatment, were imaged on day 1 of therapy. Results: In Colo205 xenografts, FOLFOX induced a profound increase in uptake of the proliferation PET tracer 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) accompanied by increases in markers for proliferation (Ki-67, thymidine kinase 1) and for activated DNA damage response (γH2AX), whereas the effect on cell death was minimal. Because tracer uptake was unaltered in the HCT116 model, these changes appear to be specific for tumor response. Conclusion: We demonstrated that 18F-FLT PET can noninvasively monitor cancer treatment-induced molecular alterations, including thymidine metabolism and DNA damage response. The cellular or imaging changes may not, however, be directly related to therapy response as assessed by volumetric measurements.
Authors: Sonja Schelhaas; Lynn Johann Frohwein; Lydia Wachsmuth; Sven Hermann; Cornelius Faber; Klaus P Schäfers; Andreas H Jacobs Journal: Mol Imaging Biol Date: 2021-11-09 Impact factor: 3.484