Therapeutic discovery for cholangiocellular carcinoma

Informazioni relative al progetto

CANDY

ID dell’accordo di sovvenzione: 101069276

DOI

10.3030/101069276

Progetto chiuso

Data della firma CE 14 Aprile 2022

Data di avvio 1 Agosto 2022

Data di completamento 31 Gennaio 2024

Finanziato da

• European Research Council (ERC)

Costo totale

Nessun dato

Contributo UE

€ 150 000,00

Coordinato da

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

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

Periodo di rendicontazione: 2022-08-01 al 2024-01-31

Sintesi del contesto e degli obiettivi generali del progetto

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.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

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.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

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.