Purpose

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.

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 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.

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 sorafenib induced microenvironment changes similar to those of rapidly growing tumors, such as a decrease in blood flow (F), fractional intravascular volume (v_p), and permeability surface area product (PS), infigratinib induced the exact opposite changes as early as day 3 after treatment: increase in F, v_p, and PS.

Conclusions

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.

中文翻译：

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动态对比增强磁共振成像作为 Infigratinib 在高 FGFR 表达肝细胞癌异种移植物中血管正常化作用的成像生物标志物。

目的

成纤维细胞生长因子受体 (FGFR) 的过度表达有助于肝细胞癌 (HCC) 的肿瘤发生、转移和不良预后。Infigratinib——一种泛 FGFR 抑制剂——部分通过改变肿瘤微环境和血管正常化来有效抑制高 FGFR 表达的 HCC 的生长。在这项研究中，我们旨在评估动态对比增强 (DCE) 磁共振成像 (MRI) 作为一种非侵入性成像技术的效用，以检测与 infigratinib 和索拉非尼治疗相关的微环境变化在高 FGFR 表达的 HCC 异种移植物中。

程序

对 12 只携带高 FGFR 表达的患者来源的 HCC 异种移植物的裸鼠进行连续 DCE-MRI 以量化载体、索拉非尼治疗前（第 0 天）和治疗后（第 3、6、9 和 15 天）的肿瘤微环境和英飞替尼。使用扩展广义动力学模型和二室分布参数模型分析 DCE-MRI 数据。治疗后，对收获的肿瘤进行免疫组织化学染色以确认 DCE-MRI 结果。

结果

到治疗第 15 天，infigratinib 诱导肿瘤消退（从基线减少 70% 的体积），而索拉非尼诱导相对生长停滞（从基线增加 185% 的体积对比从对照基线增加 694% 的体积）。DCE-MRI 分析揭示了暴露于索拉非尼与英飞替尼后微循环参数的不同变化。而索拉非尼诱导的微环境变化类似于那些快速生长的肿瘤，如在血流量的降低（的˚F），分数血容量（v _p），和表面渗透性（PS），infigratinib诱导完全相反的变化早治疗后第 3 天：F增加，v _p和PS。

结论

我们的研究表明，DCE-MRI 是一种可靠的非侵入性成像技术，用于监测高 FGFR 表达的 HCC 异种移植物中 FGFR 抑制和 VEGF 抑制的肿瘤微循环反应。此外，FGFR 抑制引起的微循环变化在治疗开始的早期就显现出来，并且被 DCE-MRI 可靠地检测到，为联合治疗创造了协同效应的可能性。