Cell circuits as targets and biomarkers for liver disease and cancer prevention

Informations projet

HEPCIR

N° de convention de subvention: 671231

DOI

10.3030/671231

Projet clôturé

Date de signature de la CE 24 Août 2015

Date de début 1 Janvier 2016

Date de fin 30 Juin 2022

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 2 305 000,00

Contribution de l’UE

€ 2 305 000,00

Coordonné par

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 4 - HEPCIR (Cell circuits as targets and biomarkers for liver disease and cancer prevention)

Période du rapport: 2020-07-01 au 2022-06-30

Résumé du contexte et des objectifs généraux du projet

Chronic liver diseases such as advanced liver disease and hepatocellular carcinoma (HCC) are major challenges for global health. HCC is the third leading and fastest rising cause of cancer death worldwide. According to the European Association for the Study of the Liver (EASL), the prevalence of liver diseases is ~6% in the EU (29 million individuals) and leads to 70,000 deaths each year. Given the growing incidence of HCC, the economic burden will significantly increase in Western populations during the next decades. There are no therapeutics available that revert fibrosis, and while in some cases liver cancer can be removed by surgery, the cancer returns in 80% of patients. For advanced HCC, the prognosis is dismal and the treatments available, only offer an extension of life by a few months. There is therefore a major unmet medical need for novel and effective therapeutics for advanced liver disease, chemoprevention and treatment of HCC. The limited availability of therapeutic options reflects our poor understanding of the molecular and clinical mechanisms involved in liver disease progression. The objective of HEPCIR was to understand the drivers of liver disease progression and to identify and develop novel therapeutic targets, biomarkers and therapeutics with the ultimate aim of impacting patient management and disease outcome for patients with advanced liver disease and HCC.

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

Within the frame of ERC ADG HEPCIR we developed a game changing cell-based system that models liver disease progression and predicts HCC risk as well as novel animal model and patient-derived systems that allowed us to: 1) decipher cell circuits involved in disease progression and carcinogenesis, 2) identify therapeutic targets, 3) develop novel biomarkers of disease progression and prediction of HCC risk for patient stratification, 4) novel therapeutics for advanced liver disease, HCC chemoprevention and treatment. Our discoveries have led to several important discoveries (123 publications in leading top level journals such as Nature, Nat Comm, Gut, Gastroenterol, J Hepatol, Cancer Cell), 6 patents and patent applications, and 118 invited talks, oral and poster communications at leading international conferences. Our discoveries have also formed the basis for the creation of Alentis Therapeutics in 2019. Alentis, is now a clinical stage biotech company that has in-licensed several of our technologies and is developing breakthrough therapies for fibrotic diseases. A CLDN1 mAb, discovered within the HEPCIR program, has entered first-in-human clinical trials in December 2021.

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)

Our program has led to important beyond state of the art discoveries. Target and drug discovery for advanced and liver disease was previously hampered by the absence of a tractable system that resembled closely what happens in patients. Within our program we have developed such a system that closely recapitulates features of disease progression and HCC risk in patients. Indeed, using this system and by combining with single cell RNaseq we uncovered several novel drivers of liver disease progression, new therapeutic targets as well as therapeutics for advanced liver disease and HCC. Furthermore, we developed novel animal model systems and patient-derived models that more closely mimic disease progression in patients and we harnessed their incredible potential to study and better understand liver disease progression drivers and to assess and validate our novel therapeutic targets and therapeutics. We also identified novel biomarkers that can help predict which patients have higher risk of progressing to HCC. Finally, the CLDN1 mAbs represent a completely novel and unique first-in-class concept for the treatment of advanced liver disease and cancer prevention. Our program has therefore led to several important advances that we expect will help improve advanced liver disease and HCC patient care.

Overview of the challenge, the ERC HEPCIR program and the key achievements