Dr Christophe GROSSET (INSERM Bordeaux)

From these initial results and following the arrival of three researchers in the team, new projects have emerged and are carried out in collaboration with bioinformaticians, chemists and French and foreign clinicians. One of these projects aims (i) to study the role of a protein, which modifies the DNA of cells and participates in the formation of the most serious tumors, and (ii) to test the effectiveness of several inhibitors of this protein, knowing that some of these inhibitors are already used clinically in the treatment of adult cancers. A second project aims to study the mechanisms of energy production by hepatoblastoma cells, to find their weak point and then to block this source of energy in order to prevent the development of tumor cells. All of this work aims to study the molecular content of the most dangerous hepatoblastomas in order to find innovative therapeutic solutions to effectively treat children with these cancers.

In a first project, with the support of the Eva pour la vie association, the team sought to block the action of beta-catenin using microRNAs, small RNAs that act as biological switches and form a new family of therapeutic molecules. Among the 1,712 microRNAs tested, she selected four (let-7i-3p, miR-449b-3p, miR-624-5p and miR-885-5p) which strongly decrease the level of beta-catenin protein and inhibit its oncogenic action in hepatoblastoma cells. The miR-624-5p microRNA is the most efficient of the four and blocks the formation of hepatoblastoma in the chick embryo. These results, which made the cover of the scientific magazine Hepatology Communications , demonstrate the interest of this tumor model for testing new therapeutic molecules in the laboratory.

In a second work, the team studied the molecular content of 25 hepatoblastoma tumors by RNA sequencing. Bioinformatics and microscopic analyzes of tumor tissues have shown the interest of the four genes HSD17B6, ITGA6, TOP2A and VIM in classifying hepatoblastomas into three different groups. In the most aggressive group called “C2A”, we have shown that the “Fanconi anemia” molecular pathway plays a very important oncogenic role and allows tumor cells to resist chemotherapy. Using an inhibitor of this pathway, we were able to stop the growth of C2A hepatoblastoma cells, destroy them and inhibit the development of hepatoblastoma in mice. These results show that this treatment, already used in the treatment of certain leukaemias in adults and children, could be used to treat children with aggressive hepatoblastoma type C2A. All of these results are summarized in the scientific magazine Hepatology .

In a third work published in the journal Oncotarget , we describe in more detail the interest of the hepatoblastoma model implemented in the chick embryo and its usefulness for testing therapeutic molecules. Our results show that in chickens, Huh6 hepatoblastoma cells form tumors quite similar to those developing in patients. This model is therefore very useful for researchers because it identically reproduces the stages of formation of a hepatoblastoma and makes it possible to easily study this cancer in the laboratory. The team also analyzed by RNA sequencing the molecular content of these tumors during their formation in chickens and identified several genes that could play an important oncogenic role. We therefore plan to study them. In conclusion, this new model will allow us to test different types of anticancer molecules and to better understand how a hepatoblastoma develops, with the key to new treatment possibilities.
Read the interview on CARENEWS (September 2018)

December 2020 Update - New Research on DIPGs (Brainstem Tumors)
Thanks to the support of Eva Pour la Vie, Pour Emma, Scott & Co and Grandir Sans Cancer, a new project will start in January 2021 within the INSERM-MIRCADE team in Bordeaux. The goal of this project is to identify new drugs capable of killing DIPG cells from a catalog of more than 900 molecules. In order to accelerate the transfer of these results to patients and facilitate the opening of new clinical trials, the anti-cancer molecules tested will either already be available in the hospital (drugs with Marketing Authorization), or in progress. evaluation (clinical trials) in the treatment of cancer in adults or children. After selecting the most promising molecules, the team will study the ability of the most effective drugs to kill DIPG cells using two DIPG tumor models in chick embryos and in mice (models put in place in the team by Dr Martin Hagedorn). The second objective of this work is to study the effect of the most efficient molecules on the behavior of DIPG cells using cellular, molecular and high resolution microscopy imaging approaches. Indeed, knowing today how these molecules act is to prepare the development of tomorrow's drugs. By choosing to test these anticancer drugs, we hope to find new therapeutic solutions to treat children with brainstem tumors.

This completely new project calls on the skills and know-how of the MIRCADE team in the GITC study (see recent publication in the journal Neuro-Oncology ) and in the search for the most effective compounds among a library of several hundred of candidates (see the 2017 publication on Childhood Liver Cancer ). This work will be carried out by Guillaume Herrault, Master 2 student at the University of Poitiers, and Farah Rahal, doctoral student in the team, under the joint supervision of Drs Christophe Grosset and Martin Hagedorn.