FGF19 overexpression

Genomic analysis of patient samples from The Cancer Genome Atlas (TCGA) confirmed that a segment of HCC patients harboring FGF19 overexpression indeed exhibited increased activation of EGFR signaling. These findings conclusively indicate that both induced and innate activation of EGFR could mediate resistance to FGFR4 inhibition, suggesting that dual blockade of EGFR and FGFR4 may be a promising future therapeutic strategy for the treatment of FGF19-FGFR4 altered HCC.

Co-activation of Met & FGF19 occurs in a significant subset of HCC patients with co-expression leading to HCC development in mice. This Met/FGF19 preclinical model provides an improved platform to test various targeted and immunotherapies.

Importantly, targeting FGF19 signaling with fisogatinib efficiently suppresses FGF19-induced liver metastasis in a mouse model. In summary, this study describes the mechanism by which FGF19 regulates CRLM, thereby providing a novel target for CRLM intervention.

Pathway inhibition was observed by increased C4, total bile acids, FGF19, and decreased total cholesterol at all dose levels. Conclusions The promising response rate and manageable safety profile from this phase I study suggest that ABSK-011 may have clinical benefit for HCC pts with prior therapies through biomarker selection of FGF19.

Efficacy studies were conducted in HCC xenograft models and mutant FGFR4-dependent xenograft models including a RMS PDX model harboring FGFR4 V550L mutation. ABSK012 demonstrated strong potency over multiple FGFR4 mutants that are insensitive to a first generation FGFR4 inhibitor BLU-554. ABSK012, presented here by Abbisko Therapeutics, is a highly potent, selective, and next-generation small molecule FGFR4 inhibitor overcoming FGFR4 mutations resistant to first-generation inhibitors. Its superior preclinical profile supports its fast-track development into clinic.

In addition, we found that ABSK011 increased CD8 + T cell infiltration in humanized HCC mouse models. Conclusions These preclinical data demonstrated that ABSK011 treatment increased IFN related response as well as CD8 + T cell infiltration in FGF19 overexpressed HCC models, supporting the combination of FGFR4 inhibitor and immune checkpoint molecules such as anti-PD-(L)1 antibodies to achieve enhanced antitumor activity.

P2, N=62, Recruiting, Abbisko Therapeutics Co, Ltd | Not yet recruiting --> Recruiting | Initiation date: Jul 2022 --> Dec 2021

P1, N=50, Recruiting, Abbisko Therapeutics Co, Ltd | Trial completion date: Jan 2023 --> Aug 2025 | Trial primary completion date: Oct 2022 --> Dec 2023

We further show that HCC patients with high levels of circulating FGF19 have a reduced natremia, indicating dipsogenic features. The present study provides evidence of a new activity of FGF19, which could be clinically relevant in the context of FGF19 overexpressing cancers and in the course of treatment of metabolic disorders by FGF19 analogues.

In summary, we describe FGF19 as a putative serum CRC biomarker that exerts novel endocrine-like paraneoplastic effects on the liver. Study limitations included the lack of FGF19 quantification in CRC patient blood, in vivo experimentation using two different cell lines, and gender-related batch effects identified by RNA sequencing.

ETV4 facilitated the recruitment and infiltration of TAMs and MDSCs through CCL2-CCR2 pathway, and either knockdown of CCL2 by lentivirus or CCR2 inhibitor CCX872 treatment impaired ETV4-induced TAMs and MDSCs infiltration and HCC metastasis . Either depletion of TAMs by clodronate liposomes or depletion of MDSCs by anti-Gr-1 attenuated ETV4- mediated HCC metastasis... ETV4 is a prognostic biomarker, and targeting this oncogenic pathway may provide a combinational therapeutic strategy to inhibit HCC metastasis .

P1, N=50, Recruiting, Abbisko Therapeutics Co, Ltd

The expression of FGF19 is significantly upregulated in NSCLC, and the overexpression of FGF19 is correlated with poor OS, especially in lung adenocarcinoma (LUAD) cases. FGF19 might serve as a potential biomarker for predicting poor OS in NSCLC patients.

Self-renewal of LCSCs were characterized by sphere formation assay, clonogenicity assay, sorafenib resistance assay and tumorigenic potential assays... FGF19/FGFR4 axis promotes the self-renewal of LCSCs via activating SOCE/NFATc2 pathway; in turn, NFATc2 transcriptionally activates FGF19 expression. Targeting this signaling circuit represents a potential strategy for improving the therapeutic efficacy of HCC.

Tumor-bearing mice were then treated with lenvatinib (LEN), or sorafenib (SOR), or vehicle until moribund. ST6GAL1 is a tumor-derived secreted protein downstream of FGF19 and may be a useful serum biomarker for identification of patients with FGF19-driven HCC who may benefit from LEN therapy.

Hepatocellular carcinoma (HCC) is a lethal cancer with limited therapeutic options, and standard therapy with sorafenib provides only modest survival benefits. 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.