Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Apr 26;16(9):1690.
doi: 10.3390/cancers16091690.

Current and Future Therapeutic Targets for Directed Molecular Therapies in Cholangiocarcinoma

Philipp Heumann  1 , Andreas Albert  1 , Karsten Gülow  1 , Denis Tümen  1 , Martina Müller  1 , Arne Kandulski  1
Affiliations
Review

Current and Future Therapeutic Targets for Directed Molecular Therapies in Cholangiocarcinoma

Philipp Heumann et al. Cancers (Basel). .

Abstract

We conducted a comprehensive review of the current literature of published data, clinical trials (MEDLINE; ncbi.pubmed.com), congress contributions (asco.org; esmo.org), and active recruiting clinical trains (clinicaltrial.gov) on targeted therapies in cholangiocarcinoma. Palliative treatment regimens were analyzed as well as preoperative and perioperative treatment options. We summarized the current knowledge for each mutation and molecular pathway that is or has been under clinical evaluation and discussed the results on the background of current treatment guidelines. We established and recommended targeted treatment options that already exist for second-line settings, including IDH-, BRAF-, and NTRK-mutated tumors, as well as for FGFR2 fusion, HER2/neu-overexpression, and microsatellite instable tumors. Other options for targeted treatment include EGFR- or VEGF-dependent pathways, which are known to be overexpressed or dysregulated in this cancer type and are currently under clinical investigation. Targeted therapy in CCA is a hallmark of individualized medicine as these therapies aim to specifically block pathways that promote cancer cell growth and survival, leading to tumor shrinkage and improved patient outcomes based on the molecular profile of the tumor.

Keywords: biliary tract cancer; cholangiocarcinoma; molecular-directed therapy; targeted therapy.

PubMed Disclaimer

Conflict of interest statement

Arne Kandulski (scientific presentations and scientific advisory activities): Roche Pharma AG, Eisai GmbH, Abbvie Germany AG, Janssen-Cilag GmbH, MSD Sharp & Dohme GmbH, Boston Scientific Corp., Fujifilm Germany, Micro-Tech Germany, Bayer Pharma AG Germany. Martina Müller (scientific presentations) Falk Foundation, Gilead Sciences, Abbvie Germany AG. All other authors have no conflicts of interests to declare.

Figures

Figure 1
Figure 1
The diagnostic algorithm for cholangiocarcinoma was modified according to EASL guidelines (European Association for the Study of the Liver), NCCN guidelines (National Comprehensive Cancer Network), and S3-Leitlinie Diagnostik und Therapie des Hepatozellulären Karzinoms und biliärer Karzinome (German guidelines); * histologic confirmation via ERCP, EUS, cholangioscopy, or liver biopsy, ** if locally available.
Figure 2
Figure 2
Treatment algorithm for CCA [9,72]. SBRT—stereotactic body radiotherapy; PDT—photodynamic therapy; iRFA—intraductal radiofrequency ablation; TACE—transarterial chemoembolization; TARE—transarterial radioembolization; TDxd—trastuzumab deruxtecan. The dashed arrows denote individual decision-making in the treatment of locally advanced CCA as a neoadjuvant treatment or conversion therapy strategy. Pointed arrows define the pathway if neoadjuvant treatment fails.
Figure 3
Figure 3
Most frequent and currently druggable molecular alterations by CCA subtype (notably, for the approval status of the potential agents, see the section below). Created with Biorender.
Figure 4
Figure 4
Key signaling pathways for FDA-approved molecular-directed drugs for the treatment of advanced CCA in the palliative setting. (A) FGFR signaling pathway. (B) IDH signaling pathway. (C) Mechanism of immune checkpoint inhibition. (D) NTRK signaling pathway. 1 Durvalumab/pembrolizumab in combination with gemcitabine/cisplatin for all-comers, pembrolizumab monotherapy for MSI-high/TMB-high. Created and modified with Biorender.
Figure 5
Figure 5
Timeline: targeted therapy with FDA approval for treatment of advanced cholangiocarcinoma. 1L: first line; 2L: second line.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. McGlynn K.A., Petrick J.L., El-Serag H.B. Epidemiology of Hepatocellular Carcinoma. Hepatology. 2021;73((Suppl. S1)):4–13. doi: 10.1002/hep.31288. - DOI - PMC - PubMed
    1. Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021;71:209–249. doi: 10.3322/caac.21660. - DOI - PubMed
    1. Razumilava N., Gores G.J. Cholangiocarcinoma. Lancet. 2014;383:2168–2179. doi: 10.1016/s0140-6736(13)61903-0. - DOI - PMC - PubMed
    1. Khan S.A., Tavolari S., Brandi G. Cholangiocarcinoma: Epidemiology and risk factors. Liver Int. 2019;39:19–31. doi: 10.1111/liv.14095. - DOI - PubMed
    1. Rizvi S., Khan S.A., Hallemeier C.L., Kelley R.K., Gores G.J. Cholangiocarcinoma—Evolving concepts and therapeutic strategies. Nat. Rev. Clin. Oncol. 2018;15:95–111. doi: 10.1038/nrclinonc.2017.157. - DOI - PMC - PubMed

Grants and funding

This research received no external funding.
-