Intrahepatic cholangiocarcinoma is a malignant tumor that arises in the ducts that collect bile in the liver and carry it to the small intestine. It is a very difficult tumour to diagnose in the early stages of development due to the absence of specific symptoms, which makes it extremely difficult for these tumours to be surgically removed, which is currently the only treatment with curative potential. Therefore, the mortality associated with this tumor is very high, and added to the increase in cases observed in recent years, it is becoming a major public health problem. Although the approval of immunotherapy has recently led to a breakthrough in the treatment of these tumours, most patients do not respond adequately, so it is necessary to look for new strategies.
In this context, the study recently published in the journal Signal Transduction and Targeted Therapy of the Springer Nature publishing house has emerged, in which a new potential treatment route has been identified to try to increase the survival of these patients. The research has been led by Dr. Javier Vaquero, leader of the Hepatobiliary Tumors Laboratory at the Cancer Research Center (CSIC-University of Salamanca), nd by Dr. Isabel Fabregat, leader of the TGF-beta and cancer group at IDIBELL, both CIBEREHD researchers. This work has been funded for the most part by the State Research Agency (AEI), the Spanish Association Against Cancer (AECC) and the CIBEREHD (of the Carlos III Health Institute).
Identification of the problem: there are inhibitors that promote tumor development
In recent years, multiple therapeutic targets have been evaluated with the aim of increasing the efficacy of immunotherapy. In this line, inhibitors of the TGF-β signaling pathway have been tested in several clinical trials due to the potent immunosuppressive role of this pathway. However, these attempts have failed.
Dr. Vaquero’s study represents an important advance in the knowledge of cholangiocarcinoma, since it proposes an explanation for these unsuccessful attempts. Traditionally, the TGF-β signaling pathway has been thought to promote the development of tumours, so many therapeutic efforts have focused on blocking it. However, this study shows that, in the case of cholangiocarcinoma, the TGF-β pathway actually slows down the growth of tumor cells, so inhibiting it directly can be harmful and favor tumor progression in certain contexts. In this context, Dr. Fabregat points out: “Our results show a very important difference with respect to other liver tumors such as hepatocellular carcinoma, which could explain the failure of clinical trials with these inhibitors.”
Key Discovery: A New Way to Block Tumor Growth
To avoid these unwanted effects, the researchers have focused their efforts on two proteins, NOX4 and NOX1, which are specifically expressed in a cell type within the tumor microenvironment, cancer-associated fibroblasts, which support and feed tumor cells. Research has shown that simultaneous inhibition of these two proteins with the drug Setanaxib is able to slow down tumour progression in preclinical models, without negatively affecting tumour cells or other tissues. The use of this dual NOX4/NOX1 inhibitor makes it possible to specifically target the tumor microenvironment, weakening the support that the tumor needs to grow and resist treatments.
The results in cell cultures and animal models show a significant reduction in tumor growth and an improvement in the infiltration of beneficial immune cells, which could enhance the efficacy of immunotherapy in future studies by the group led by Dr. Vaquero. “Setanaxib is a molecule with a lot of potential that is already being tested clinically in other tumors with similar characteristics, which could accelerate its possible application in patients with cholangiocarcinoma. ” In addition, our study opens the door to new therapeutic combinations that could improve the survival and quality of life of patients,” says Dr. Vaquero.
International effort
In addition to the experimental effort carried out by Drs. Ester González-Sánchez and Josep Amengual, belonging to the groups of Dr. Vaquero and Dr. Fabregat, this research is the result of a national and international and multidisciplinary collaboration, which has involved numerous centers of excellence in biomedicine and oncology belonging to collaborative national networks, such as CIBEREHD, and the European Network for the Study of Cholangiocarcinoma (ENS-CCA) and the COST Action CA22125 – Precision BTC Network. This national and international synergy demonstrates the need for collaboration to achieve scientific excellence and quality translational research.
The Bellvitge Biomedical Research Institute (IDIBELL) is a research centre created in 2004 specialising in cancer, neuroscience, translational medicine and regenerative medicine. It has a team of more than 1,500 professionals who, from the 73 research groups, generate more than 1,400 scientific articles per year. IDIBELL is owned by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona and the City Council of L’Hospitalet de Llobregat.
IDIBELL is a member of the Campus of International Excellence of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centres accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the “HR Excellence in Research” program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Centre of the AECC Scientific Foundation (FCAECC).