The anti-angiogenic agent lenvatinib induces tumor vessel normalization and enhances radiosensitivity in hepatocellular tumors

Abstract

The evaluation of angiogenesis inhibitors requires the analysis of the precise structure and function of tumor vessels. The anti-angiogenic agents lenvatinib and sorafenib are multi-target tyrosine kinase inhibitors that have been approved for the treatment of hepatocellular carcinoma (HCC). However, the different effects on tumor vasculature between lenvatinib and sorafenib are not well understood. In this study we analyzed the effects of both drugs on vascular structure and function, including vascular normalization, and investigated whether the normalization had a positive effect on a combination therapy with the drugs and radiation using micro X-ray computed tomography with gold nanoparticles as a contrast agent, as well as immunohistochemical analysis and interstitial uid pressure (IFP) measurement. In mice subcutaneously transplanted with mouse HCC cells, treatment with lenvatinib or sorafenib for 14 days inhibited tumor growth and reduced the tumor vessel volume density. However, analysis of integrated data on vessel density, rates of pericyte-covering and perfused vessels, tumor hypoxia, and IFP measured 4 days after drug treatment showed that treatment with 3 mg/kg of lenvatinib signi cantly reduced the microvessel density and normalized tumor vessels compared to treatment with 50 mg/kg of sorafenib. These results showed that lenvatinib induced vascular normalization and improved the intratumoral microenvironment in HCC tumors earlier and more effectively than sorafenib.Moreover, such changes increased the radiosensitivity of tumors and enhanced the effect of lenvatinib and radiation combination therapy, suggesting that this combination therapy is a powerful potential application against HCC.

The Impact of Lenvatinib on Tumor Blood Vessel Shrinkage of Hepatocellular Carcinoma during Treatment: An Imaging-Based Analysis

“…CT scans showed no significant decrease in the volume density of TBVs at this point. In addition, the authors reported a significant decrease in the volume density of TBVs on day 14 of lenvatinib administration [4]. DOI: 10.1159/000526976 Therefore, we propose that the shrinkage of the TBV diameter that we confirmed in patients over a short period of time may be a process of normalizing the abnormally dilated TBVs.…”

“…Lenvatinib, a multi-tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFR) 1–3, fibroblast growth factor receptors (FGFR) 1–3, rearranged during transfection (RET), mast/stem cell growth factor receptor kit (SCFR), and platelet-derived growth factor receptor (PDGFR) beta [ 2 , 3 ], is available for the treatment of unresectable HCC. In vivo studies have shown that lenvatinib strongly inhibits VEGFR and FGFR, resulting in a marked normalization of tumor blood vessels (TBVs) [ 4 ].…”

Efficacy of rechallenge transcatheter arterial chemoembolization after lenvatinib treatment for advanced hepatocellular carcinoma

“…44,45 Recently, Une et al reported that LEN treatment induced vascular normalization and improved the intratumoral microenvironment in HCC tumors earlier and more effectively than sorafenib treatment. 46 This mechanism will improve the distribution of Lipiodol ® mixed in combination with anticancer drugs and enhance the therapeutic effect of TACE. The effectiveness of combination therapy with sorafenib and TACE for HCC has been reported.…”

Lenvatinib dose, efficacy, and safety in the treatment of multiple malignancies

“…Inhibition of angiogenesis by lenvatinib has been shown to result in normalization of tumor vasculature, which may increase delivery and uptake of chemotherapy into cancer cells [ 32 , 33 ]; and in preclinical studies, lenvatinib monotherapy showed activity in chemotherapy-resistant human tumor xenografts [ 34 ]. Chemotherapy has a direct antitumor effect but also has the capacity to promote antitumor immunogenicity via the release of tumor-associated antigens and the maturation of antigen-presenting cells, resulting in activation of cytotoxic T cells ( Figure 1B ) [ 35 , 36 ].…”