Targeted strategies for prevention and treatment of fibrosis-associated liver cancer

Informations projet

FIBCAN

N° de convention de subvention: 101021417

DOI

10.3030/101021417

Date de signature de la CE 27 Septembre 2021

Date de début 1 Juillet 2022

Date de fin 30 Juin 2027

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 2 430 000,00

Contribution de l’UE

€ 2 430 000,00

Coordonné par

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 2 - FIBCAN (Targeted strategies for prevention and treatment of fibrosis-associated liver cancer)

Période du rapport: 2024-01-01 au 2025-06-30

Résumé du contexte et des objectifs généraux du projet

Advanced liver diseases represent a major global health challenge. Liver cancer is the 3rd deadliest cancer worldwide, with an alarming rise of affected patient and mortality in the last decades. Viral and metabolic liver disease are the main risk factors for HCC, which nearly always arises in advanced liver fibrosis. For metabolic liver disease approved therapies are absent. Cure or suppression of viral infection cannot eliminate the HCC risk in patients with advanced fibrosis. Despite significant progress, therapeutic options for established HCC are still limited in efficacy and safety. Importantly, patient survival in HCC is dependent on the underlying fibrotic liver disease which is not targeted by approved HCC therapies. Addressing these unmet medical needs, FIBCAN aims to identify urgently needed targets for prevention and treatment of fibrosis-driven liver cancer.

We have previously discovered a therapeutic target for prevention and treatment of fibrosis-driven HCC: Claudin-1. Based on preliminary data suggesting that Claudin-1 is implicated in liver fibrosis and hepatocarcinogenesis, and overall and liver-specific patient death, the first objective of FIBCAN is to investigate its role in the progression of the disease. Furthermore, FIBCAN aims to discover and validate novel targets, by exploiting state-of-the-art platforms and models developed in our laboratory.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

We investigated the role of CLDN1 in the progression of liver and biliary cancer on a cellular level, and assessed the impact of CLDN1 – and CLDN1 mAbs treatment – on the tumor microenvironment. We confirmed the potential of CLDN1 mAbs in several in vitro and in vivo model and gained a better understanding on the underlying cellular mechanisms.
Furthermore, by harnessing cell-based systems, and scRNA-seq, we identified novel targets for advanced liver disease and HCC, which are currently under investigation.

Key results have been reported in several high-impact peer-reviewed journals, including JCI Insight (2022), Science Translational Medicine (2022), Journal of Hepatology (2023), Nature Communication (2024), Journal of Hepatology (2025).

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

Considering the lack of treatment for liver cancer and critical need for such, CLDN1 mAbs represent a great hope for a first in line treatment against liver fibrosis and cancer. Our efforts to understand it’s mechanisms combined with clinical transition ensured by a pharmaceutical partner advances the research in liver disease beyond the state-of-the-art.

New targets identified in complement to CLDN1 open the scope for further research, new therapeutics and a better understanding of the overall picture of liver disease progressing to cancer. In the second period, we will provide mechanistic insights related to their involvement in disease progression and confirm their relevance as therapeutic target.