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DISSECTING THE HINDRANCE OF HEDGEHOG PATHWAY IN INTRAHEPATIC CHOLANGIOCARCINOMA: A STEP TOWARDS TARGETED THERAPY

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Introduction

Cholangiocarcinoma (CCA) comprises a heterogeneous group of cancers affecting the biliary tree and is considered one of the deadliest cancers. CCA incidence and mortality are increasing dramatically worldwide in the last decades. CCA prognosis is dismal (5-year survival rate <20%) due to various aspects including late diagnosis, poor response to chemotherapy and lack of well-established targeted therapeutic options. One of the foremost patho-biological features of CCA is the high inter- and intra-tumoral heterogeneity, which has limited the discovery of biomarkers and novel therapeutic alternatives, hampering the development of tools for early diagnosis and effective treatment, with unfavorable implications on patient outcome. From an anatomical outlook, CCA is classified into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA). Furthermore, iCCA shows distinct histological subtypes which led the World Health Organization (ICD-O-3.2) to categorize it into small and large bile duct-type. Noteworthy, thus far no data exist concerning the correlation of molecular traits and specific iCCA subtypes. Indeed, this marked heterogeneity strikingly restricts the possibility of translational research and represents an utmost aspect to be scrutinized. The Hedgehog (Hh) pathway is one of the molecular networks involved in the pathogenesis of iCCA. As a matter of fact, it is fundamental in various hallmarks of iCCA, including tumor growth, survival, migration, cancer stem cells activation and epithelial-mesenchymal transition. In the light of these observations, targeting this cascade for therapeutic purposes in iCCA is possible owing to evidence of Hh's pathogenetic role in the disease.

Aims & Methods

This study aims to evaluate, in vitro, in primary and established cell lines, a novel natural chemical compound called Glabrescione B (GlaB) that specifically inhibits Gli1, a transcriptional factor downstream of Hh pathway.
Using Trypan Blue Exclusion test, the dose- and time-dependent response of free GlaB and hyaluronic acid (HA)-encapsulated GlaB (HA-GlaB) has been evaluated. MTS assay has been performed to determine the IC₅₀. Western blot has been used to analyze the target protein expression levels. Wound-healing assay has been achieved to assess the cell migration. Colony formation assay has been performed to rate the colony-forming ability of cancer cells. Flow cytometry analysis has been accomplished to investigate cell death. The results were confirmed in at least three independent experiments and the quantitative data were reported as the mean ± SEM. Student’s t-tests for paired samples were used to assess differences among two groups. A p-value of <0.05 was considered statistically significant (*p<0.05;**p<0.01;***p<0.001).

Results

Our findings demonstrate that both free GlaB and HA-GlaB treatments significantly reduce iCCA cell rate viability, migration, colony-forming ability, and Gli1 levels in a dose- and time-dependent manner (0.05<p<0.001), leading to a decisive decrease in cancer cells invasiveness. Ultimately, compared to controls, early evidence from flow cytometry reveals an induction of necrosis and apoptosis as a result of drug administration.

Conclusion

Hedgehog pathway dysregulation is well known to be correlated with the development and progression of various cancers, including iCCA. A novel natural compound, named Glabrescione B, is able to inhibit cancer cells growth, survival, invasiveness and to induce cancer cell death. Taken together, these data provide insight into a new and potentially beneficial natural compound for the management of iCCA in vivo.

References

1. Banales JM. et al., Nat Rev Gastroenterol Hepatol. 2020 Sep;17(9):557-588. Epub 2020 Jun 30. PMID: 32606456.
2. Bertuccio P. et al., J Hepatol. 2019 Jul;71(1):104-114. Epub 2019 Mar 23. PMID: 30910538.
3. European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL-ILCA Clinical Practice Guidelines on Intrahepatic Cholangiocarcinoma. J Hepatol. 2023 Mar 22:S0168-8278(23)00185-X. Epub ahead of print. PMID: 37084797.
4. Riedlinger D. et al., J Hepatobiliary Pancreat Sci. 2014 Aug;21(8):607-15. Epub 2014 Apr 15. PMID: 24733827.
5. Cigliano A. et al., Expert Opin Ther Targets. 2017 May;21(5):471-483.1310842. Epub 2017 Mar 30. PMID: 28326864.
6. Razumilava N. et al., J Hepatol. 2014 Mar;60(3):599-605. Epub 2013 Nov 14. Erratum in: J Hepatol. 2014 Jul;61(1):185. PMID: 24239776.
7. Infante P, et al., Cancer Lett. 2021 Feb 28;499:220-231. Epub 2020 Nov 26. PMID: 33249196.

DISSECTING THE HINDRANCE OF HEDGEHOG PATHWAY IN INTRAHEPATIC CHOLANGIOCARCINOMA: A STEP TOWARDS TARGETED THERAPY

Savino Paradiso 1, Guido Carpino 1, Paola Infante 1, Lucia Di Marcotullio 1, Deborah Quaglio 1, Chiara Di Meo 1, MATTEO FRANCHITTO 1, Teresa De Luca 1, Bruno Botta 1, Eugenio Gaudio 1, Domenico Alvaro 1, Vincenzo Cardinale 1

1 Sapienza - University of Rome, Rome, Italy

Event

UEG Week Vienna 2024

Topics

Digestive Oncology Endoscopy Mechanisms & Personalised Medicine Hepatobiliary

Submission format

Abstract

Session

Diagnose and treat to target in GI cancer: Latest news

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

UEG Presentation

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Panel discussion: Cholangiocarcinoma secrets unveiled

Event

UEG Postgraduate Teaching Programme Berlin 2025

Topics

Digestive Oncology Endoscopy Hepatobiliary Surgery

Session

Cholangiocarcinoma secrets unveiled

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

UEG Presentation

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Summary: Cholangiocarcinoma secrets unveiled

Marianna Arvanitakis 1

1 ERASME University Hospital, Université Libre de Bruxelles, Brussels, Belgium

Event

UEG Postgraduate Teaching Programme Berlin 2025

Topics

Digestive Oncology Endoscopy Hepatobiliary Surgery

Session

Cholangiocarcinoma secrets unveiled

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

UEG Presentation

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Advances in oncological treatment for cholangiocarcinoma

Karen Geboes 1

1 Ghent University Hospital, St-Amandaberg (Gent), Belgium

Event

UEG Postgraduate Teaching Programme Berlin 2025

Topics

Digestive Oncology Endoscopy Hepatobiliary Surgery

Session

Cholangiocarcinoma secrets unveiled

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

UEG Standards and Guidelines

Clinical Practice Guideline

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Summary

Intrahepatic cholangiocarcinoma (iCCA) develops inside the liver, between bile ductules and the second-order bile ducts. It is the second most frequent primary liver cancer after hepatocellular carcinoma, and its global incidence is increasing. It is associated with an alarming mortality rate owing to its silent presentation (often leading to late diagnosis), highly aggressive nature and resistance to treatment. Early diagnosis, molecular characterisation, accurate staging and personalised multidisciplinary treatments represent current challenges for researchers and physicians. Unfortunately, these challenges are beset by the high heterogeneity of iCCA at the clinical, genomic, epigenetic and molecular levels, very often precluding successful management. Nonetheless, in the last few years, progress has been made in molecular characterisation, surgical management, and targeted therapy. Recent advances together with the awareness that iCCA represents a distinct entity amongst the CCA family, led the ILCA and EASL governing boards to commission international experts to draft dedicated evidence-based guidelines for physicians involved in the diagnostic, prognostic, and therapeutic management of iCCA.

Keywords

Diagnosis, intrahepatic cholangiocarcinoma, management, risk factors, staging, targeted therapy

EASL-ILCA Clinical Practice Guidelines on the management of intrahepatic cholangiocarcinoma

Publisher

European Association for the Study of the Liver

Guideline

Clinical Practice Guideline

Topics

Digestive Oncology Hepatobiliary

Citation

Journal of Hepatology, July 2023. vol. 79, 181–208

Published

2023

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CCC: Molecular targeted therapies

Arndt Vogel 1

1 Medizin. Hochschule Hannover, Hannover, Canada

Event

UEG Week Berlin 2025

Topics

Digestive Oncology Hepatobiliary Mechanisms & Personalised Medicine Radiology & Imaging

Session

Advancement in management of primary liver tumors

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

UEG Poster

Standard Poster

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Introduction

Cholangiocarcinoma (CCA) constitutes a heterogeneous group of epithelial malignancies that arise in the biliary tree. CCA is a very aggressive cancer and carries a poor prognosis¹. Furthermore, in view of the constant increase in its incidence and mortality in recent decades throughout the world, it represents a growing global health problem^1,2. CCAs are divided into three subtypes according to their anatomical site of origin: intrahepatic CCA (iCCA), perihilar (pCCA), and distal (dCCA). Specifically, iCCA is characterize by high intertumoral clinical-pathological and molecular heterogeneity, leading to an innovative histological classification approved by WHO (ICD-O-3.2), into small bile duct iCCA and large bile duct iCCA³. The molecular pathogenesis of iCCA is very intricate and involves multiple molecular networks: among them, the Hedgehog (Hh)^4,6 signaling pathway. Indeed, the Hh pathway plays an important role in many aspects of iCCA, such as tumor survival, proliferation, migration and EMT reprogramming⁵. The impact of innovative therapies on the survival of patients with iCCA is an ongoing area of investigation. Evidence on the pathogenetic role of Hh in iCCA implies the possibility of targeting this signaling pathway for therapeutic purposes in iCCA subtypes.

Aims & Methods

The aim of this study is to demonstrate the antitumor efficacy of a natural therapeutic compound, from an in-house library, that inhibits the Hh pathway in experimental models of human iCCA, in vitro, in established iCCA cell lines (CCLP1) and primary cell lines derived from small or large bile duct iCCA. The iCCA samples from resected specimens have been processed by mechanical and enzymatic digestion to obtain patient-derived primary cell lines. The effect of Glabrescione B (GlaB), a selective inhibitor of GLI1 (Hh downstream transcriptional factor), has been evaluated. The dose-dependent efficacy of GlaB [0, 1, 5, 10, 20, 50 μM] or hyaluronic acid (HA) nanohydrogel-encapsulated Glab [0, 0.5, 1, 5, 10 μM], have been evaluated by Trypan Blue Exclusion Test and MTS assay (cell viability), at different time points (24h, 48h, 72h, 96h). Its ability as inhibitor of Hh signaling pathway has been evaluated by Western Blot analysis. All experiments have been conducted in N.3 experimental replicates.

Results

Our research shows a dose-dependent and time-dependent reduction of cell proliferation by Trypan Blue Exclusion Test in all cell lines (p<0.05). The decrease already occurs at low concentrations and at 24-hour incubation (40-50%) and becomes more evident at higher concentrations and at 96-hour incubation (80-90%) (p<0.05). Likewise, at the protein level, Gli1 knockdown, in a dose and time-dependent manner, is demonstrated (p<0.05). MTS assays confirmed the cytotoxicity effect of GlaB at 20 μM and 50 μM (p<0.05). Therefore, we decided to pursue the study with lower concentrations (from 1 μM to 10 μM) capable of knocking down the cell viability by 50%. Thereafter, successful, and stable encapsulation of GlaB [0.5-10 μM] in HA nanohydrogel has been accomplished. Data showed a dose-dependent and time-dependent inhibitory activity of HA-encapsuled GlaB [0.5-10 μM] in all cell lines (p<0.05).

Conclusion

Aberrant Hh pathway activation is widely known to be closely related with the development and malignant progression of various human cancers. Preclinical experimental data denote that dysregulation of this pathway is a determinant of cholangiocarcinoma progression and invasiveness. The achievements of this study could lay the groundwork for pre-clinical studies of HA-encapsuled Glab in iCCA.

References

1. Banales JM. et al., Nat Rev Gastroenterol Hepatol. 2020 Sep;17(9):557-588. Epub 2020 Jun 30. PMID: 32606456; PMCID: PMC7447603.
2. Bertuccio P. et al., J Hepatol. 2019 Jul;71(1):104-114. Epub 2019 Mar 23. PMID: 30910538.
3. European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL-ILCA Clinical Practice Guidelines on Intrahepatic Cholangiocarcinoma. J Hepatol. 2023 Mar 22:S0168-8278(23)00185-X. Epub ahead of print. PMID: 37084797.
4. Riedlinger D. et al., J Hepatobiliary Pancreat Sci. 2014 Aug;21(8):607-15. Epub 2014 Apr 15. PMID: 24733827.
5. Cigliano A. et al., Expert Opin Ther Targets. 2017 May;21(5):471-483.1310842. Epub 2017 Mar 30. PMID: 28326864.
6. Razumilava N. et al., J Hepatol. 2014 Mar;60(3):599-605. Epub 2013 Nov 14. Erratum in: J Hepatol. 2014 Jul;61(1):185. PMID: 24239776; PMCID: PMC3944428.