Combined inhibition of FGFR4 and VEGFR signaling enhances efficacy in FGF19 driven hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is an aggressive liver malignancy that is difficult to treat with no approved biomarker based targeted therapies. FGF19-FGFR4 signaling blockade has been recently identified as a promising avenue for treatment of a subset of HCC patients. Using HCC relevant xenograft and PDX models, we show that Lenvatinib, an approved multi-kinase inhibitor, strongly enhanced the efficacy of FGFR4 inhibitor H3B-6527. This enhanced combination effect is not due to enhanced FGFR4 inhibition and it is likely due to cell non-autonomous VEGFR activity of Lenvatinib. This cell non-autonomous mode of action was further supported by strong in vivo combination efficacy with the mouse specific VEGFR2 antibody, DC101, which cannot cell-autonomously inhibit pathways in human xenografts. Mechanistic studies showed that the combination resulted in enhanced efficacy through increased anti-angiogenic and anti-tumorigenic activities. Overall, our results indicate that this combination can be a highly effective treatment option for FGF19 driven HCC patients, and provide preclinical validation of a combination that can be readily tested in the clinical setting.

 

Comments:

Thank you for providing detailed information about the research findings related to hepatocellular carcinoma (HCC) and the potential treatment strategy involving the combination of Lenvatinib and FGFR4 inhibitor H3B-6527. Based on the information provided, here is a summary of the key points:

1. **Background**: Hepatocellular carcinoma (HCC) is an aggressive liver malignancy without approved targeted therapies based on specific biomarkers.

2. **Promising Treatment Avenue**: FGF19-FGFR4 signaling blockade has emerged as a promising treatment approach for a subset of HCC patients.

3. **Study Approach**: Researchers used relevant models, including xenograft and patient-derived xenograft (PDX) models, to investigate the efficacy of combining Lenvatinib (a multi-kinase inhibitor) and FGFR4 inhibitor H3B-6527 in treating HCC.

4. **Enhanced Efficacy**: The study demonstrated that Lenvatinib significantly enhanced the efficacy of H3B-6527 in HCC models. This enhanced effect was not solely due to increased FGFR4 inhibition.

5. **Cell Non-Autonomous Mechanism**: The enhanced combination effect was attributed to the cell non-autonomous activity of Lenvatinib, particularly its impact on VEGFR (vascular endothelial growth factor receptor) pathways.

6. **Anti-Angiogenic and Anti-Tumorigenic Activities**: Mechanistic studies revealed that the combination treatment increased anti-angiogenic (inhibiting the formation of new blood vessels) and anti-tumorigenic (inhibiting tumor growth) activities, contributing to its effectiveness.

7. **Clinical Implications**: The study suggests that this combination therapy could be highly effective for HCC patients with FGF19-driven tumors. The findings provide preclinical validation for a combination treatment approach that could be explored in clinical trials.

In summary, this research highlights a potentially promising treatment strategy for a specific subset of HCC patients, offering new hope in the fight against this aggressive liver cancer. Further clinical studies will be essential to confirm the efficacy and safety of this combination therapy in human patients.

Related Products

Cat.No.	Product Name	Information
S8675	H3B-6527	H3B-6527 is a highly selective covalent FGFR4 inhibitor with an IC50 value of <1.2 nM and at least 250-fold selectivity over FGFR1-3 (IC50 values of 320, 1,290 and 1,060 nM respectively).

Related Targets

FGFR