Therapeutic discovery for cholangiocellular carcinoma

Informacje na temat projektu

CANDY

Identyfikator umowy o grant: 101069276

DOI

10.3030/101069276

Projekt został zamknięty

Data podpisania przez KE 14 Kwietnia 2022

Data rozpoczęcia 1 Sierpnia 2022

Data zakończenia 31 Stycznia 2024

Finansowanie w ramach

• European Research Council (ERC)

Koszt całkowity

Brak danych

Wkład UE

€ 150 000,00

Koordynowany przez

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 1 - CANDY (Therapeutic discovery for cholangiocellular carcinoma)

Okres sprawozdawczy: 2022-08-01 do 2024-01-31

Podsumowanie kontekstu i ogólnych celów projektu

Cholangiocarcinoma (CCA) is one of the deadliest cancers comprising a heterogeneous cluster of malignancies that are distinct to hepatocellular carcinoma (HCC) and that can emerge at any point in the biliary tree. CCA is mostly diagnosed very late resulting in aggressive disease progression, poor treatment response, and dismal prognosis with a median survival of less than 2 years. Curative hepatic resection is an option in a minority of patients with frequent recurrence. For most patients, diagnosis will occur when the disease is already too advanced, and the only options are chemotherapies or palliative care. Current standard-of-care for CCA is unsatisfactory with very limited efficacy and adverse effects. Recently approved second-line therapeutics (e.g. Pemigatinib, a fibroblast growth factor receptor inhibitor, and Ivosidenib, an isocitrate dehydrogenase 1 (IDH1) mutant inhibitor) can improve outcome. However, these are only suited to a small subset of CCA patients and have significant adverse effects. Thus, there is a major unmet medical need for novel therapeutic strategies to improve patient outcome. Claudin-1 (CLDN1) is a transmembrane protein expressed in tight junctions, but exposed at the cell surface on cancer epithelial cells. The aim of CANDY was to investigate the CLDN1 as a therapeutic target in preclinical proof-of-concept studies based on monoclonal antibodies and models characterized or established within ERC FIBCAN.

Prace wykonane od początku projektu do końca okresu sprawozdawczego oraz najważniejsze dotychczasowe rezultaty

Proof-of-concept studies were performed in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse as well as patient CCA organoid models. Targeting exposed CLDN1 demonstrated a robust anti-tumoral effect across intra-and extra-hepatic CCA mouse models, with a significant inhibition of metastatic disease. Functional studies in patient-derived CCA organoids led to decreased cellular viability and altered cancer cell plasticity and fate. Mechanistically, our proposed treatment suppressed gene expression of pathways mediating proliferation, stemness and EMT by inhibiting oncogenic signaling.
A publication presenting these results is in preparation.

Innowacyjność oraz oczekiwany potencjalny wpływ (w tym dotychczasowe znaczenie społeczno-gospodarcze i szersze implikacje społeczne projektu)

These results demonstrate that Claudin-1 is a CCA driver and therapeutic target. The proof-of-concept studies in patient-derived models pave the way for the clinical development of a novel treatment to improve the outcomes of patients with advanced CCA. Moreover, the understanding of the role of Claudin-1 and its mechanism of action paves the way towards the exploration of similar treatments in other malignancies.