Hepatocellular carcinoma (HCC), one of the leading causes of cancer-related death, develops from premalignant lesions in chronically damaged livers. Although it is well established that FGF19 acts through the receptor complex FGFR4-b-Klotho (KLB) to regulate bile acid metabolism, FGF19 is also implicated in the development of HCC. In humans, FGF19 is amplified in HCC and its expression is induced in the liver under cholestatic and cirrhotic conditions. In mice, ectopic overexpression of FGF19 drives HCC development in a process that requires FGFR4. In this study, we describe an engineered FGF19 (M70) that fully retains bile acid regulatory activity but does not promote HCC formation, demonstrating that regulating bile acid metabolism is distinct and separable from tumorpromoting activity. Mechanistically, we show that FGF19 stimulates tumor progression by activating the STAT3 pathway, an activity eliminated by M70. Furthermore, M70 inhibits FGF19-dependent tumor growth in a rodent model. Our results suggest that selectively targeting the FGF19-FGFR4 pathway may offer a tractable approach to improve the treatment of chronic liver disease and cancer. Cancer Res; 74(12); 3306-16. Ó2014 AACR.

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Hepatic accumulation of bile acids is central to the pathogenesis of cholestatic liver diseases. Endocrine hormone fibroblast growth factor 19 (FGF19) may reduce hepatic bile acid levels through modulation of bile acid synthesis and prevent subsequent liver damage. However, FGF19 has also been implicated in hepatocellular carcinogenesis, and consequently, the potential risk from prolonged exposure to supraphysiological levels of the hormone represents a major hurdle for developing an FGF19-based therapy. We describe a nontumorigenic FGF19 variant, M70, which regulates bile acid metabolism and, through inhibition of bile acid synthesis and reduction of excess hepatic bile acid accumulation, protects mice from liver injury induced by either extrahepatic or intrahepatic cholestasis. Administration of M70 in healthy human volunteers potently reduces serum levels of 7α-hydroxy-4-cholesten-3-one, a surrogate marker for the hepatic activity of cholesterol 7α-hydroxylase (CYP7A1), the enzyme responsible for catalyzing the first and rate-limiting step in the classical bile acid synthetic pathway. This study provides direct evidence for the regulation of bile acid metabolism by FGF19 pathway in humans. On the basis of these results, the development of nontumorigenic FGF19 variants capable of modulating CYP7A1 expression represents an effective approach for the prevention and treatment of cholestatic liver diseases as well as potentially for other disorders associated with bile acid dysregulation.

Cancer is the second leading cause of death globally, and despite the advances in drug development, it is still necessary to develop new plant-derived medicines. Compared with using conventional chemical drugs to decrease the side effects induced by chemotherapy, natural herbal medicines have many advantages. The present study aimed to discover the potential cytotoxicity of ethanol extract and its derived fractions (chloroform, ethyl acetate, butanol, and aqueous) of Adenosma bracteosum Bonati. (A. bracteosum) on human large cell lung carcinoma (NCI-H460) and hepatocellular carcinoma (HepG2). Among these fractions, the chloroform showed significant activity in the inhibition of proliferation of both cancerous cells because of the presence of bioactive compounds including xanthomicrol, 5,4’-dihydroxy-6,7,8,3’-tetramethoxyflavone, and ursolic acid which were clearly revealed by nuclear magnetic resonance spectroscopy (1H-NMR, 13C-NMR, Heteronuclear Multiple Bond Coherence, and Heteronuclear Single Quantum Coherence Spectroscopy) analyses. According to the radical scavenging capacity, the 5,4’-dihydroxy-6,7,8,3’-tetramethoxyflavone compound (AB2) exhibited the highest anticancer activity on both NCI-H460 and HepG2 with IC50 values of 4.57 ± 0.32 and 5.67 ± 0.09 µg/mL respectively, followed by the ursolic acid with the lower percent inhibition at 13.05 ± 0.55 and 10.00 ± 0.16 µg/mL, respectively (p < 0.05). Remarkably, the AB2 compound induced to significant increase in the production of reactive oxygen species accompanied by attenuation of mitochondrial membrane potential, thus inducing the activation of caspase-3 activity in both human lung and liver cancer cells. These results suggest that A. bracteosum is a promising source of useful natural products and AB2 offers opportunities to develop the novel anticancer drugs.

Background: NGM313 is a humanized monoclonal antibody activator of β-klotho/FGFR1c that has been shown to reduce HOMA-IR in obese subjects. This study compared the effects of a single dose of NGM313 vs. daily pioglitazone (PIO) on insulin sensitivity, liver fat content (LFC) and lipids in insulin resistant, obese subjects with increased liver fat. Methods: 25 subjects were randomized 2:1 to either a single dose of NGM313 240 mg SC (n=17) or PIO 45 mg PO QD (n=8) for 36 days. Whole-body insulin sensitivity was determined by a two-step hyperinsulinemic, euglycemic clamp and LFC by magnetic resonance imaging-proton density fat fraction (MRI-PDFF). Results: (Table 1) A single dose of NGM313 significantly increased glucose disposal rate and was comparable to PIO. Suppression of endogenous glucose production was enhanced by both NGM313 and PIO. Significant reductions in LFC, HbA1c, serum triglycerides and LDL-C, and an increase in HDL-C, were observed with NGM313. NGM313 produced a greater reduction in LFC vs. PIO at day 23. The safety and tolerability profile was favorable for both drugs. Conclusion: NGM313 is a potent insulin sensitizer, comparable to PIO. In addition, NGM313 is highly effective in reducing LFC in subjects with increased liver fat. As such, NGM313 has significant potential to be an effective treatment for nonalcoholic steatohepatitis and type 2 diabetes. Disclosure A. DePaoli: Employee; Self; NGM Biopharmaceuticals. V. Phung: Employee; Self; NGM Biopharmaceuticals. Stock/Shareholder; Self; NGM Biopharmaceuticals. M.R. Bashir: Consultant; Self; RadMD. Research Support; Self; Madrigal Pharmaceuticals, Metacrine Inc, NGM Biopharmaceuticals, Pinnacle Clinical Research, ProSciento, Siemens Corporation. L. Morrow: Employee; Spouse/Partner; Eli Lilly and Company. Employee; Self; ProSciento. C. Beysen: None. A. Yan: None. L. Ling: Employee; Self; NGM Biopharmaceuticals. Stock/Shareholder; Self; NGM Biopharmaceuticals. B. Baxter: Employee; Self; NGM Biopharmaceuticals. K.L. Luskey: Consultant; Self; NGM Biopharmaceuticals. J.M. Olefsky: None.