FGF401 and vinorelbine synergistically mediate antitumor activity and vascular normalization in FGF19-dependent hepatocellular carcinoma

Abstract

Liver cancer: combining two drugs for improved therapeutic effect The drugs FGF401 and vinorelbine, when working together synergistically, could be effective in treating those liver cancers driven by the activity of the fibroblast growth factor 19 (FGF19) protein. The drugs' effects on human tumors grafted into mice were studied by an international research team led by Hung Huynh at the National Cancer Centre in Singapore. FGF401 is a small molecule that inhibits the activity of the receptor protein that the FGF19 growth factor interacts with to promote some cancers. Vinorelbine disrupts protein microtubules required for the cell division that allows cancer cells to multiply. In combination, the drugs achieved significantly enhanced anti-cancer effects which can now be tested in clinical trials. The research also uncovered new details of FGF401's therapeutic actions, including its ability to restore healthy blood vessel formation. Hepatocellular carcinoma (HCC) is a lethal cancer with limited therapeutic options, and standard therapy with sorafenib provides only modest survival benefits. Fibroblast growth factor 19 (FGF19) has been proposed as a driver oncogene, and targeting its receptor, FGFR-4, may provide a better alternative to standard therapy for patients with FGF19-driven tumors. Sixty-three HCC patient-derived xenograft (PDX) models were screened for FGF19 expression. Mice bearing high and low FGF19-expressing tumors were treated with FGF401 and/or vinorelbine, and the antitumor activity of both agents was assessed individually and in combination. Tumor vasculature and intratumoral hypoxia were also examined. High FGF19 expression was detected in 14.3% (9 of 63) of the HCC models tested and may represent a good target for HCC treatment. FGF401 potently inhibited the growth of high FGF19-expressing HCC models regardless of FGF19 gene amplification. Furthermore, FGF401 inhibited the FGF19/FGFR-4 signaling pathway, cell proliferation, and hypoxia, induced apoptosis and blood vessel normalization and prolonged the overall survival (OS) of mice bearing high FGF19 tumors. FGF401 synergistically acted with the microtubule-depolymerizing drug vinorelbine to further suppress tumor growth, promote apoptosis, and prolong the OS of mice bearing high FGF19 tumors, with no evidence of increased toxicity. Our study suggests that a subset of patients with high FGF19-expressing HCC tumors could benefit from FGF401 or FGF401/vinorelbine treatment. A high level of FGF19 in a tumor may serve as a potential biomarker for patient selection.