Dynamic Contrast-Enhanced Magnetic Resonance Imaging as Imaging Biomarker for Vascular Normalization Effect of Infigrati
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RESEARCH ARTICLE
Dynamic Contrast-Enhanced Magnetic Resonance Imaging as Imaging Biomarker for Vascular Normalization Effect of Infigratinib in High-FGFR-Expressing Hepatocellular Carcinoma Xenografts Anh Tran,1 Tong San Koh,1 Aldo Prawira,2 Rebecca Zhi Wen Ho,2 Thi Bich Uyen Le,2 Thanh Chung Vu,2 Septian Hartano,1 Xing Qi Teo,3 Way Cherng Chen,4 Philip Lee,3 Choon Hua Thng,1 Hung Huynh 2 1
Department of Oncologic Imaging, National Cancer Centre, Singapore, Singapore Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore 3 Functional Metabolism Group, Agency for Science, Technology and Research, Singapore BioImaging Consortium, Singapore, Singapore 4 Bruker Singapore Pte Ltd, Singapore, Singapore 2
Abstract Purpose: Overexpression of fibroblast growth factor receptor (FGFR) contributes to tumorigenesis, metastasis, and poor prognosis of hepatocellular carcinoma (HCC). Infigratinib—a panFGFR inhibitor—potently suppresses the growth of high-FGFR-expressing HCCs in part via alteration of the tumor microenvironment and vessel normalization. In this study, we aim to assess the utility of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) as a non-invasive imaging technique to detect microenvironment changes associated with infigratinib and sorafenib treatment in high-FGFR-expressing HCC xenografts. Procedures: Serial DCE-MRIs were performed on 12 nude mice bearing high-FGFR-expressing patient-derived HCC xenografts to quantify tumor microenvironment pre- (day 0) and posttreatment (days 3, 6, 9, and 15) of vehicle, sorafenib, and infigratinib. DCE-MRI data were analyzed using extended generalized kinetic model and two-compartment distributed parameter model. After treatment, immunohistochemistry stains were performed on the harvested tumors to confirm DCE-MRI findings. Results: By treatment day 15, infigratinib induced tumor regression (70 % volume reduction from baseline) while sorafenib induced relative growth arrest (185 % volume increase from baseline versus 694 % volume increase from baseline of control). DCE-MRI analysis revealed different changes in microcirculatory parameters upon exposure to sorafenib versus infigratinib. While
Electronic supplementary material The online version of this article (https:// doi.org/10.1007/s11307-020-01531-7) contains supplementary material, which is available to authorized users. Correspondence to: Choon Hua Thng; e-mail: [email protected], Hung Huynh; e-mail: [email protected]
Tran A. et al.: Imaging biomarker for vascular normalization effect of Infigratinib
sorafenib induced microenvironment changes similar to those of rapidly growing tumors, such as a decrease in blood flow (F), fractional intravascular volume (vp), and permeability surface area product (PS), infigratinib induced the exact opposite changes as early as day 3 after treatment: increase in F, vp, and PS. Conclusions: Our study demonstrated that DCE-MRI is a reliable non-invasiv
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