Jonathan Deleon

Background:  Cholangiocarcinoma (CCA) is an extremely deadly cancer that occurs in the biliary system.¹ The different types of cholangiocarcinoma include intrahepatic CCA (iCCA), perihilar CCA (pCCA), and distal CCA (dCCA).¹This type of cancer is classified as either fluke derived or non-fluke derived.¹ There are about 5000 new cases of patients being diagnosed with this type of cancer each year, and only 2% of people diagnosed with this type of cancer survive more than 5 years.² Surgical resection is the first line treatment for this type of cancer growth.¹ However, it is only effective in cases where the cancer is caught in the early stages.¹ Other medications that have shown that they could be used as a treatment option include Pemigatinib and Lenvatinib.^3,4 Although a variety of treatment options are available, researchers have struggled to find a reliable remedy for treating this type of metastatic growth. There are a variety of different animal models being used to study new treatment options, but a consistent model has not been found yet.⁵ Given the pressing need for new therapeutic agents, researchers have been focusing on targeting the fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR) pathways for new treatment options.⁶

Objective:  This narrative review aims to review current literature that focuses on targeting the FGFR and VEGFR pathways to treat iCCA.

Search Methods:  An online PubMed search was done to identify relevant articles between 2019 and 2024 using the following MeSH terms: “Cholangiocarcinoma,” “FGFR inhibitors,” “VEGFR inhibitors,” and “Treatment”.

Results:  The results of the literature review indicated that dually inhibiting the FGFR and VEGFR pathways using novel therapeutic agents could be used as an effective treatment option in stopping lymphangiogenesis and tumor cell proliferation in iCCA.⁶ Using the medications Infigratinib and SAR131675 to stop iCCA growth worked synergistically to halt cancer growth.⁶ Additionally, other studies have demonstrated that people with both wild type and mutant FGFR genes have been diagnosed with iCCA.⁷ This finding demonstrates the importance of finding treatment options that could work well for patients based on their gene functions.⁷ Another medication approved called Pemigatinib, a selective FGFR gene inhibitor, has been shown to halt tumor progression for an average of 8.7 months.⁸ Lenvatinib, a non-selective FGFR gene inhibitor, has also been studied in patients resistant to Pemigatinib treatment.⁴ The results of this study indicated that patients being treated with this medication displayed an average survival rate of 7.35 months.⁴

Conclusion:  The synergistic effects of targeting the FGFR and VEGFR pathways in iCCA treatment demonstrate a promising new treatment option that could be implemented in the future. Although these studies provide valuable insights into various therapeutic options involved in iCCA, more research needs to be done that focuses on the molecular interactions between the various genes and pathways involved in this type of cancer growth. Additionally, future studies that highlight why dually inhibiting the FGFR and VEGFR pathways help stop lymphangiogenesis could be a key in determining the next steps in researching new therapeutic options.

Works Cited:

1. Brindley PJ, Bachini M, Ilyas SI, et al. Cholangiocarcinoma. Nat Rev Dis Primers. 2021;7(1):65. doi:10.1038/s41572-021-00300-2
2. Roy S, Glaser S, Chakraborty S. Inflammation and Progression of Cholangiocarcinoma: Role of Angiogenic and Lymphangiogenic Mechanisms. Frontiers in Medicine. 2019;6. https://www.frontiersin.org/articles/10.3389/fmed.2019.00293
3. Spahn S, Kleinhenz F, Shevchenko E, et al. The molecular interaction pattern of lenvatinib enables inhibition of wild-type or kinase-mutated FGFR2-driven cholangiocarcinoma. Nat Commun. 2024;15(1):1287. doi:10.1038/s41467-024-45247-6
4. Ueno M, Ikeda M, Sasaki T, et al. Phase 2 study of lenvatinib monotherapy as second-line treatment in unresectable biliary tract cancer: primary analysis results. BMC Cancer. 2020;20(1):1105. doi:10.1186/s12885-020-07365-4
5. Loeuillard E, Fischbach SR, Gores GJ, Rizvi S. Animal models of cholangiocarcinoma. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease. 2019;1865(5):982-992. doi:10.1016/j.bbadis.2018.03.026
6. Peng M, Li H, Cao H, et al. Dual FGFR and VEGFR inhibition synergistically restrain hexokinase 2-dependent lymphangiogenesis and immune escape in intrahepatic cholangiocarcinoma. J Gastroenterol. 2023;58(9):908-924. doi:10.1007/s00535-023-02012-8
7. Brandi G, Relli V, Deserti M, et al. Activated FGFR2 signalling as a biomarker for selection of intrahepatic cholangiocarcinoma patients candidate to FGFR targeted therapies. Sci Rep. 2024;14(1):3136. doi:10.1038/s41598-024-52991-8
8. Parisi A, Delaunay B, Pinterpe G, et al. Pemigatinib for patients with previously treated, locally advanced or metastatic cholangiocarcinoma harboring FGFR2 fusions or rearrangements: A joint analysis of the French PEMI-BIL and Italian PEMI-REAL cohort studies. Eur J Cancer. 2024;200:113587. doi:10.1016/j.ejca.2024.113587