Dynamic Contrast-Enhanced Magnetic Resonance Imaging as Imaging Biomarker for Vascular Normalization Effect of Infigratinib in High-FGFR-Expressing Hepatocellular Carcinoma Xenografts

Autor: Septian Hartano, Philip Lee, Choon Hua Thng, Tong San Koh, Rebecca Zhi Wen Ho, Aldo Prawira, Way Cherng Chen, Hung Huynh, Xing Qi Teo, Anh Tran, Thanh Chung Vu, Thi Bich Uyen Le
Rok vydání: 2020
Předmět:
Sorafenib
Cancer Research
Carcinoma
Hepatocellular
Imaging biomarker
FGFR Inhibition
Contrast Media
Antineoplastic Agents
Apoptosis
Mice
SCID
030218 nuclear medicine & medical imaging
Metastasis
03 medical and health sciences
0302 clinical medicine
medicine
Biomarkers
Tumor
Tumor Microenvironment
Animals
Humans
Radiology
Nuclear Medicine and imaging
skin and connective tissue diseases
Cell Proliferation
Tumor microenvironment
medicine.diagnostic_test
Neovascularization
Pathologic
business.industry
Phenylurea Compounds
Liver Neoplasms
Magnetic resonance imaging
medicine.disease
Magnetic Resonance Imaging
Receptors
Fibroblast Growth Factor
Xenograft Model Antitumor Assays
Perfusion
Kinetics
Pyrimidines
Oncology
Hepatocellular carcinoma
Cancer research
Immunohistochemistry
business
medicine.drug
Zdroj: Molecular imaging and biology. 23(1)
ISSN: 1860-2002
Popis: Overexpression of fibroblast growth factor receptor (FGFR) contributes to tumorigenesis, metastasis, and poor prognosis of hepatocellular carcinoma (HCC). Infigratinib—a pan-FGFR 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. 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 post-treatment (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. 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 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. Our study demonstrated that DCE-MRI is a reliable non-invasive imaging technique to monitor tumor microcirculatory response to FGFR inhibition and VEGF inhibition in high-FGFR-expressing HCC xenografts. Furthermore, the microcirculatory changes from FGFR inhibition manifested early upon treatment initiation and were reliably detected by DCE-MRI, creating possibilities of combinatorial therapy for synergistic effect.
Databáze: OpenAIRE
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