A Catalan research team has managed to reproduce in the laboratory how some tumours associated with neurofibromatosis type 1 (NF1) evolve into aggressive malignant forms, an advance that could help develop new treatments for this rare genetic disease. In addition, the study, led by researchers from the Germans Trias i Pujol Research Institute (IGTP), in collaboration with IDIBELL and ICO, published in Nature Communications, has made it possible to identify a possible therapeutic combination with potential for the treatment of these tumours, combining two drugs: olaparib and selumetinib.
This study is part of the research efforts in rare diseases, a strategic area for IDIBELL through the REMMA program (Bellvitge Research in Rare Adult Diseases), which promotes translational research to improve the diagnosis and treatment of unprevalent pathologies, such as neurofibromatosis type 1.
Neurofibromatosis type 1: a rare disease with unmet needs
Neurofibromatosis type 1 affects approximately one in 3,000 people and is an inherited genetic disease that predisposes to the development of peripheral nervous system tumours. People with NF1 can develop benign tumors called neurofibromas, which in some cases evolve into malignant peripheral nerve sheath tumors (MPNST), a type of cancer that is very aggressive and difficult to treat.
Until now, understanding how this malignant transformation occurs has been one of the great challenges of NF1 research, especially in the context of rare diseases, where there is often a lack of suitable experimental models.
A pioneering model for reproducing tumour progression
To address this, the researchers created an innovative model from genetically modified human stem cells. This system allows the different phases of tumour progression to be reproduced in the laboratory and to study the molecular mechanisms involved in the process, from benign stages to malignant forms.
The results show that the loss of a key mechanism of genetic regulation, known as PRC2, is decisive for tumors to acquire malignant characteristics. “This work has allowed us to reproduce in the laboratory, for the first time and in a very precise way, the progression of tumours associated with neurofibromatosis type 1 from benign stages to malignant forms”, explains Eduard Serra, IGTP researcher and co-lead author of the study. “This helps us to better understand what mechanisms drive this transformation and offers us a new platform to identify possible therapeutic strategies,” adds Meritxell Carrió, the other co-lead author of the study.
New therapeutic opportunities
In addition, based on the model, the research team screened hundreds of therapeutic compounds and managed to identify a possible specific vulnerability of malignant tumors associated with NF1. In preclinical experiments, the combination of the drugs olaparib and selumetinib managed to significantly reduce tumor growth, opening new avenues for the development of treatments in these patients.
“The transformation of neurofibromas into malignant tumours is an extremely complex and difficult process to study”, explains Itziar Uriarte, first author of the work, which was part of her doctoral thesis. “The model developed has allowed us not only to study how malignant transformation occurs in NF1, but also to identify potential therapeutic vulnerabilities,” adds Conxi Lázaro, co-leader of the Hereditary Cancer group at IDIBELL and ICO and member of REMMA Bellvitge.
The researchers stress that these types of models can help accelerate the identification of new therapies for tumors that currently have few treatment options.
Collaborative research with translational impact
The study has been carried out with the collaboration of the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) of the United States, and has been funded by La Marató de TV3, the Children’s Tumor Foundation (CTF) and the Carlos III Health Institute.
This work exemplifies the value of collaborative research to advance in the knowledge and treatment of rare diseases, one of the key axes of IDIBELL through the REMMA program, aimed at transferring the results of basic research to clinical practice and improving the quality of life of patients.
The Bellvitge Biomedical Research Institute (IDIBELL) is a research centre created in 2004 and specialising in cancer, neuroscience, translational medicine and regenerative medicine. It has a team of more than 1,500 professionals who, from 73 research groups, publish more than 1,400 scientific articles a year. L’IDIBELL is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Health Institute, 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 d’Excelencia Internacional 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).