Theranostics 2020; 10(8):3518-3532. doi:10.7150/thno.40687

Research Paper

Concurrent imaging of vascularization and metabolism in a mouse model of paraganglioma under anti-angiogenic treatment

Caterina Facchin1, Mailyn Perez-Liva1, Anikitos Garofalakis1,2, Thomas Viel1, Anais Certain1, Daniel Balvay1, Thulaciga Yoganathan1, Justine Woszczyk1, Kelly De Sousa1, Joevin Sourdon1, Jean Provost3,4, Mickael Tanter5, Charlotte Lussey-Lepoutre1,6, Judith Favier1, Bertrand Tavitian1,7✉

1. Université de Paris, PARCC, INSERM, F-75015 Paris, France
2. BiospaceLab, F-95960 Nesles-la-vallée, France
3. Engineering physics, Polytechnique Montréal, Montréal, QC, Canada
4. Montreal Heart Institute, Montreal, QC, Canada
5. Physics for Medicine Paris (INSERM U1273, ESPCI Paris, PSL University, CNRS FRE 2031), Inserm Technology Research Accelerator for Biomedical Ultrasound, F-75012 Paris, France
6. Sorbonne Université, Department of nuclear medicine, AP-HP, Pitie-Salpêtrière Hospital, F-75013 Paris, France
7. Radiology Department, AP-HP Centre, Hôpital Européen Georges Pompidou, F-75015 Paris, France

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Citation:
Facchin C, Perez-Liva M, Garofalakis A, Viel T, Certain A, Balvay D, Yoganathan T, Woszczyk J, De Sousa K, Sourdon J, Provost J, Tanter M, Lussey-Lepoutre C, Favier J, Tavitian B. Concurrent imaging of vascularization and metabolism in a mouse model of paraganglioma under anti-angiogenic treatment. Theranostics 2020; 10(8):3518-3532. doi:10.7150/thno.40687. Available from http://www.thno.org/v10p3518.htm

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Abstract

Rationale: Deregulation of metabolism and induction of vascularization are major hallmarks of cancer. Using a new multimodal preclinical imaging instrument, we explored a sequence of events leading to sunitinib-induced resistance in a murine model of paraganglioma (PGL) invalidated for the expression of succinate dehydrogenase subunit B (Sdhb-/-).

Methods: Two groups of Sdhb-/- tumors bearing mice were treated with sunitinib (6 weeks) or vehicle (3 weeks). Concurrent Positron Emission Tomography (PET) with 2′ -deoxy-2′-[18F]fluoro-D-glucose (FDG), Computed Tomography (CT) and Ultrafast Ultrasound Imaging (UUI) imaging sessions were performed once a week and ex vivo samples were analyzed by western blots and histology.

Results: PET-CT-UUI enabled to detect a rapid growth of Sdhb-/- tumors with increased glycolysis and vascular development. Sunitinib treatment prevented tumor growth, vessel development and reduced FDG uptake at week 1 and 2 (W1-2). Thereafter, imaging revealed tumor escape from sunitinib treatment: FDG uptake in tumors increased at W3, followed by tumor growth and vessel development at W4-5. Perfused vessels were preferentially distributed in the hypermetabolic regions of the tumors and the perfused volume increased during escape from sunitinib treatment. Finally, initial changes in total lesion glycolysis and maximum vessel length at W1 were predictive of resistance to sunitinib.

Conclusion: These results demonstrate an adaptive resistance of Sdhb-/- tumors to six weeks of sunitinib treatment. Early metabolic changes and delayed vessel architecture changes were detectable and predictable in vivo early during anti-angiogenic treatment. Simultaneous metabolic, anatomical and functional imaging can monitor precisely the effects of anti-angiogenic treatment of tumors.

Keywords: Cancer metabolism, angiogenesis, paraganglioma, SDHB, multimodality imaging, positron emission tomography, ultrafast-ultrasound imaging