Testimony of Dr Marie Castets

"Nearly 500 children in France and 80,000 around the world die each year from cancer. 50 years ago, less than 25% were cured. The situation has greatly improved with the advent of chemotherapy, initially developed. for adults but benefited children. It is estimated that 3 in 4 children are currently recovering. Yet one in 4 children will not recover and this situation has not improved much since the early 2000s. current treatments remain aggressive and are the cause of more or less disabling sequelae in a large number of children.

The duty of a pediatric oncologist is to provide care while preserving the quality of life as much as possible. It is therefore urgent to understand the specificities of childhood and adolescent cancers, and to identify their molecular causes in order to imagine new treatments, more effective and less aggressive for developing organisms.

Our current research project falls within this perspective and aims to understand the mechanisms behind the resistance of tumor cells to death. Indeed, when a cell becomes abnormal, localizes outside its tissue or is in excess, it is normally eliminated by the activation of signals leading to its own death. The ability to resist the onset of this suicide is one of the characteristics acquired by tumor cells. In addition, blocking these cell death programs is implicated in resistance to treatment.

In order to improve the medical management of cancers in children, our project aims to identify the anomalies at the origin of these mechanisms of resistance to cell death and to develop new compounds that could be used as drugs. to restore it.

Our strategy is based on 2 main axes:
1) carrying out so-called large-scale studies to establish a mapping of blocking points in cell death, in particular in response to treatments;
2) the characterization of the role of the abnormalities identified in the transformation of normal cells into tumor cells and their definition as new therapeutic targets, thanks to analyzes on different cellular models, in particular three-dimensional.

Thanks to the support of Eva pour la Vie and other associations, we are currently developing these lines of research on rhabdomyosarcomas, osteosarcomas and neuroblastomas. The dynamic and exhaustive mapping of cell death pathways is in progress for these 3 cancers. Two candidate genes are being studied in rhabdomyosarcoma, in order to define whether they actually constitute activatable molecular levers to restore cell death in these tumors, and thus imagine new therapeutic avenues. "

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.

Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents with 150 new cases per year. Thanks to the progress of chemotherapy coupled with the optimization of surgical techniques, the cure rate reaches 60 to 70% for patients with non-metastatic osteosarcoma.

Unfortunately these tumors have a very strong propensity to metastasize, especially in the lungs. When diagnosing bone, lung metastases are already present in more than 20% of patients. Metastases indicate the severity of the disease. Indeed, patients with metastatic or recurrent bone respond poorly to current treatments and the cure rate in these patients has remained very low and unchanged for 30 years. It is therefore essential and essential to develop effective treatments for all these situations of therapeutic impasse and also to improve the quality of life of these young patients during and after the treatments.

Recognizing and eliminating cancer cells represent physiological functions of the immune system which are performed by specialized cells of the organism, leukocytes and in particular the population of T lymphocytes. The state of activation of T lymphocytes is permanently dependent on the balances between activating and inhibiting signals called immune checkpoints (activators or inhibitors). These immune checkpoints, which function as security locks, are essential both for optimizing the activation of T lymphocytes (activator checkpoints) and for preventing the risk of the immune system running away (inhibitory checkpoints). Cancer cells have developed multiple strategies to escape the immune system and in particular to deregulate inhibitory immune checkpoints in order to prevent the destruction of tumor cells by the immune system. The pharmaceutical industry has marketed antibodies and / or small chemical molecules which are capable of modulating some of these immune checkpoints and in fact making it possible to optimize the response of the immune system directed against the tumor.

Recent work in immuno-oncology has marked a major turning point in the understanding of the defense mechanisms of tumors against the immune system and have highlighted immune checkpoints as potential new therapeutic targets for antitumor. Treatments using this strategy in patients with metastatic melanoma have given extraordinary results in terms of cure and give new hope for other cancers. Today, therapies targeting immune checkpoints are given in many cancers, and are in clinical trial phase in osteosarcoma. The first results do not currently allow us to offer an effective treatment, in particular for the most aggressive osteosarcomas. It is therefore necessary to continue research research aimed at better understanding the interactions between cancer cells and immune cells involved in the progression of osteosarcomas.

The project funded by Eva Pour la vie (2017-2018, € 30,000) fits into this context. Its objective was to evaluate, in a preclinical model of pulmonary metastases from osteosarcoma, the effects of treatments combining two complementary immunotherapy strategies, one aimed at promoting selective recruitment of leukocytes in the tumor, the other aimed at neutralize 4 inhibitory immune checkpoints namely CTLA4, PD1, PDL1 and TIM3. This project consisted in testing different combinations of treatments with antibodies blocking inhibitory checkpoints (Ab anti-checkpoints) in the presence of fractalkine (FKN) allowing the recruitment of lymphocytes in the tumor.

Initially, the work carried out thanks to Eva pour la vie's first funding showed that the treatment of mice with FKN alone slowed the progression of pulmonary metastases from osteosarcoma by 40 to 60%, but over time , the animals eventually escaped treatment with FKN. However even though the mice metastasized in the presence of FKN, the mice were objectively in better shape than the untreated mice.

Regarding the treatments with blocking Ab at the PD1, PDL1, CTLA4 or TIM-3 checkpoints, the effects were on the one hand modest (at best a reduction of 5 to 30% in the progression of metastases) and on the other hand always lower. to those obtained with the FKN alone. In addition, we did not observe any cumulative effects of treatments combining anti-checkpoint Ab and FKN. The transcriptomic analysis of the tumors obtained in the different treatment situations (FKN + an inhibitory anti checkpoint Ab) indicated to us that the FKN had indeed enabled the recruitment of lymphocytes in the tumors but, and moreover, while certain obstacles had been lifted. by the Ac anti checkpoints, others were still active. Secondly, we associated treatment with FKN with several inhibitory anti-checkpoint antibodies. The results are disappointing since in all the combinations tested there were no more significant effects in terms of tumor reduction than FKN alone. Against all expectations, the transcriptomic analysis nevertheless revealed to us that in certain combinations, the 4 inhibitory checkpoints tested were neutralized.

The antibodies targeting CTLA4, PD1, PDL1 and TIM3 represented the first “wave” of commercialization of anti-immune checkpoint treatments. Today, antibody treatments targeting other inhibitory immune checkpoints are commercially available and in particular GAL9, LAG3 and Vista, and in fact represent new therapeutic hopes for osteosarcoma. In addition, all of our results led us to believe that the lymphocytes which were recruited into the tumor thanks to the FKN could, perhaps and also, present a defect of activation, limiting them in their capacity to destroy, cancer cells over time. This therefore led us to reconsider the combinations of immunotherapy that could be envisaged and in particular to test combinations of treatments associating FKN with blocking antibodies of inhibitory immune checkpoints and / or with stimulating antibodies of activating immune checkpoints. This study is in progress and is entirely carried out thanks to the second financial support provided by "Eva pour la Vie" (2019-2020, € 20,000)

The ultimate goal of our project being of course to offer as quickly as possible, to patients with metastatic bone, the most effective treatment possible and with the fewest side effects.

First of all, the team developed a new tumor model of DIPG in the chick embryo that makes it possible to test different anticancer drugs on the growth of tumor cells and obtain the result in a few days. It also makes it possible to evaluate the oncogenic role of certain genes in these tumors, including a very promising gene discovered by the team.

One of the promising drugs in the treatment of brainstem tumors, Panobinostat has been tested in clinical trials to assess its effectiveness in patients. Dr. Hagedorn's lab has identified two proteins whose expression increases sharply when DIPG cells are treated with Panobinostat. One of these two proteins plays an important role in the proliferation of DIPG cells and their ability to invade normal brain tissue. It is therefore likely that DIPG cells produce these two proteins to escape the harmful action of panobinostat. A major publication was written by the team and published by the world reference journal " Neuro-oncology ".

In addition, the project led by Farah Rahal under the leadership of Dr Martin Hagedorn aims to improve the treatment of children with brainstem tumors. These tumors, which are resistant to current chemotherapy regimens, generally have genome abnormalities called "epigenetic changes". The presence of these abnormalities makes brainstem tumor cells potentially sensitive to certain drugs capable of targeting these epigenetic alterations. One of these drugs targets the EZH2 protein which is heavily produced by brainstem glioma cells. The laboratory has shown that blocking the EZH2 protein by this drug leads to a decrease in the proliferation and migration of tumor cells and leads to their final elimination.

The team is testing a new chemotherapy approach which consists of "enclosing" the active anti-EZH2 molecule in a chemical envelope which will then be transported in inert form by the bloodstream to the tumor where it will be specifically released and eliminate the cells. tumors without affecting the normal tissues lining the blood vessels, in order to limit their toxicity and increase their effectiveness.

"We wish to thank the Eva Association for Life, the Groupama Health Foundation, the other parent associations and all the donors for making this project come true. We hope the results of our work will benefit children with this cancer. "

Publication (November 2019)
HDAC inhibition induces expression of scaffolding proteins critical for tumor progression in pediatric glioma: focus on EBP50 and IRSp53
https://www.ncbi.nlm.nih.gov/pubmed/31711240
https://doi.org/10.1093/neuonc/noz215

Why did you choose to focus your research on childhood cancer?

This is a huge question that I have had the opportunity to think about a lot in recent years because it comes up often. I tend to think that it was the circumstances of life that led me to pediatric oncology research, and it is the passion that keeps me from doing anything else in my life now. When I was 12, I suffered from quite severe facial paralysis and had to be hospitalized in a pediatric oncology department because there was a suspicion of a brain tumor. Looking back over the years, I think that this experience left a deep mark on me and when I left the hospital, safe and sound, I probably had a form of "survivor syndrome" which pushed me, unconsciously, towards this professional path. In addition, I had certain learning facilities and I took great pleasure in studying. It is therefore naturally that I headed for long studies. And finally, when I was a Master 2 student, I had the chance to be supervised by 2 exceptional young researchers, Dr Manon Carré and Dr Nicolas André, who both transmitted to me their passion for pediatric oncology.

Can you tell us about the team that works with you?

The research team to which I belong (Structural Biology and Integrated Chemistry-Biology) within the Marseille Cancer Research Center aims to identify new therapeutic targets by focusing on protein-protein interactions. Within this team, I lead a small group that focuses on drug repositioning. This group is made up of a thesis student, pharmacy intern Jérémy Ariey-Bonnet, who works mainly on glioblastoma (an incurable brain tumor) and a Master 2 student, Rébecca Aim, whose research project is focused on acute myeloid leukemia. My short-term objective is to recruit staff (students, engineers and post-docs) in order to be able to further develop my research projects in pediatric oncology. In addition, I work very closely with the nursing teams of the Hematology and Pediatric Oncology department of the Hôpital de la Timone, and in particular Prof. Nicolas André, with whom I design most of my research projects in order to facilitate the transfer to the clinic and thus guarantee the real-world application of our laboratory research.

Concretely, what is the use of the money entrusted by the association Eva pour la vie? Is this an important help for you, for your project?

The financial support that I receive from the Eva pour la vie association is absolutely vital to my research activity. It is very simple. Without this support, my research projects on childhood cancer would simply be on standby for lack of funding (despite more than 10 funding requests submitted each year). The money entrusted to me will allow me to pay for the consumables necessary to carry out the experiments essential for transferring our results to the clinic. We have in fact identified several drugs, used in clinics for applications as varied as arterial hypertension, parasitic infections or certain psychiatric disorders, which were able to increase the effectiveness of standard treatments against certain forms of cancer of the prostate. 'child. We must now validate these results in order to be able to set up clinical trials. It's at this crucial stage that Eva's Lifetime Support comes in.

The EPLV association is at the initiative of a process aimed at obtaining from the State a law guaranteeing a fund dedicated to research on cancers and incurable diseases of the child, as well as an improvement of aid to families. She is also co-founder of the Federation Grandir sans Cancer, at the origin of a manifesto that you have co-signed. What do you think of these initiatives?

I fully support the efforts of EPLV and the Federation Grandir sans Cancer because I believe that they are absolutely essential. It is very sad to say but the fact is that one of the main drivers of medical research remains the prospect of financial profits for the pharmaceutical industry and the biotechnology companies. Not many people know this, but private companies fund the vast majority of clinical trials around the world. When working on drugs that are no longer patented, for applications in pediatric oncology (and therefore a very small potential economic market compared to adult cancers such as breast, prostate or lung cancers) , it becomes extremely complicated to obtain financing. And setting up clinical trials becomes an even greater challenge. It is therefore the role of the State to replace private companies and guarantee targeted funding for research that may have an impact on public health, but which has little prospect of immediate financial benefits.


November 2019
The support provided by the Eva pour la vie association has enabled Eddy Pasquier's team to undertake 2 complementary approaches to identify the molecular targets of two classes of drugs with promising anti-cancer properties: beta-blockers and antihelminthics. from the class of benzimidazoles. The first approach, called in silico, is based on the use of a predictive algorithm while the second is based on the use of click chemistry. Their mass spectrometry analyzes have made it possible to identify several new therapeutic targets in gliomas and neuroblastoma. The results open important perspectives not only for the characterization of the anti-cancer mechanisms of action of drugs in general, but also for the understanding of the biology of tumors of the central and peripheral nervous system.
Click here for the detailed report .


November 2020: A new study in the fight against glioblastoma

A new publication on the role of mebendazole and the antihelminthic MAPK14 (p38alpha) in the fight against glioblastoma has just been published on the scientific journal Molecular Oncology: https://febs.onlinelibrary.wiley.com/doi/10.1002/1878- 0261.12810

Eddy Pasquier's team decided to explore the mechanism of action of this drug, which is currently reused for the treatment of brain tumors (3 clinical trials in progress) by using an algorithm in order to predict new molecular targets for this drug.
The algorithm works by first looking for compounds with similar structures and chemical characteristics (among 607,659 molecules), then querying ChEMBL (or ChEMBLdb, a manually organized chemical database of bioactive molecules with drug-like properties. ) to list all known molecular targets. This generated a list of 21 putative molecular targets for mebendazole, four of which had previously been shown to be modulated by drugs of the same pharmacological class. Of these targets, 12 were significantly upregulated in glioblastoma compared to normal brain tissue, including 4 major kinases: VEGFR2 / KDR, MAPK1 / ERK2, ABL1 and MAPK14 / p38alpha.
As the kinase activity of KDR had already been shown to be inhibited by mebendazole, Dr. Eddy Pasquier's team focused their experiments on the 3 other kinases (MAPK1, ABL1 and MAPK14).
The analyzes revealed that mebendazole could inhibit all 3 kinases, with a particularly high potency against MAPK14. The team then used a panel of biophysical and biochemical tests to characterize the interaction of mebendazole with MAPK14. Thermal displacement assay (TSA), isothermal titration calorimetry (ITC), and nanoscale differential scanning fluorimetry (nanoDSF) all confirmed that mebendazole can interact directly with MAPK14.
Molecular modeling predicted how mebendazole interacts with the catalytic site of MAPK14 to inhibit its kinase activity and the nanoBRET assay was used for orthogonal validation in living glioblastoma cells. Finally, RNA interference was used to stop the expression of MAPK14 in glioblastoma cells and revealed that this kinase is involved in the growth of tumor spheroids and the response to treatment with mebendazole.
This study suggests that targeting MAPK14 with mebendazole or other pharmacological inhibitors represents a promising strategy to improve the efficacy of chemotherapy in cancer, including the efficacy of temozolomide against glioblastoma. This project was financially supported by the Eva pour la vie association and the A * MIDEX Foundation.

The results are alarming. 100% of the places where people live, frequented by children, pregnant women, etc. are
contaminated, by 11 to 21 different pesticides. In each of the homes and in the classroom, molecules classified as carcinogenic, reprotoxic and / or endocrine disrupting have been detected. In more than 70% of the samples, we find pesticides banned, some for more than 10 years, such as DIURON, in quantities up to 60 times greater than the limit of quantification.

The associations expect effective measures from communities and the State, such as banning the spreading of non-organic products near homes, with appropriate support for farmers and winegrowers, so that the safety of children and pregnant women and inhabitants is improved, while accelerating the economic development of this prestigious sector.

• Download the HAPPI report , on the presence of pesticides in schools and places where children live .
• Consult the bill proposed by Loïc Prudhomme , Member of Parliament for Gironde , aimed at protecting the population from pesticides by establishing a buffer zone .

- Research funding
The creation of a public research fund dedicated to childhood cancer, leukemia and incurable diseases, guaranteed by law. An additional fund of 15 to 20 million euros / year, allocated to research on childhood cancer, as well as an equivalent amount on other rare incurable childhood diseases would make it possible to finance projects on which needs are critical. First step forward: in 2018, the government (Ministry of Research) allocated 5 million euros per year for this research. But this insufficient sum only makes it possible to support too few projects.

- Help for families of sick children
We propose a law establishing a status of "protected parent" for parents whose child is diagnosed with a serious illness. Objectives: to provide specific protections in terms of employment, housing (rent, credit) and tax administration. The amounts of aid granted to families of sick children should be greater, and based on the actual duration of the child's illness. In 2021, we obtained the doubling of the duration of the AJPP (daily parental presence allowance), increased from 310 days to 620 days. A mission also demonstrated the need to provide assistance to families of sick children more simply, more quickly.

- Help for families of deceased children
We asked for the establishment of an automatic death benefit that would be paid to the parents in the event of a child death (3400 euros), as well as various protective measures for families having lost a child. In 2020, a law aimed at better supporting these families was passed unanimously, taking up several of our requests: death capital (2000 euros), maintenance of social assistance, protection against dismissal, psychological support ... https://www.legifrance.gouv.fr/jorf/id/JORFTEXT000041975976

- Reception conditions for hospitalized children
Set up regular independent audits in pediatric departments, in particular pediatric oncology, with the collaboration of associations and families of patients (systematic questionnaires actually used). These audits would make it possible both to help the nursing teams and to improve reception conditions (medical, food, etc.) and treatment of children.

- Bone marrow, platelets, blood donation
The Ministry of Research and Higher Education could participate in improving the policy of information and incentive to donate blood, platelets and bone marrow - by including these concepts in school learning, primary up to high school or even higher education. Hours of health-related lessons could be provided by teachers, specialized associations and health professionals. Similar actions can be envisaged within French companies, with facilities adapted to volunteers.

The findings are more or less the same for other types of incurable childhood illnesses. Finally, parents often encounter serious social difficulties, which can be easily resolved.

That is why we are asking for the study of a bill dealing with the following themes:

- Set up public research funding dedicated to pediatric cancer & leukemia , in the amount of 20 million euros, guaranteed by law. An equivalent amount would also be allocated to other incurable childhood illnesses. Several possible funding methods have been identified.

- Facilitate the individualization of treatments , in particular in the case of diseases where there is no curative therapy. Collaboration with international colleagues whose medical approach could bring results must be facilitated.

- Improve the quality of reception & treatment of children in hospitals . The establishment of regular independent audits in pediatric departments, with the collaboration of associations and above all, of the families of patients would make it possible to provide assistance to staff and patients, and to prevent possible abuses.

- Reform the daily parental presence allowance for parents of seriously ill children , in order to increase it to the level of the minimum wage or to 80% of the salary. In addition, we are asking for the extension of the death benefit for those under 18 (this measure already exists for the beneficiaries of deceased employees, unemployed etc ..., up to € 3,400 paid by the CPAM)

Family of Yanelle, 5 years old
When our daughter's diagnosis was announced, and unable to accept that such a terrible disease could affect a 5-year-old girl, I turned to the internet, hoping to find comfort, and came across the site of Eva pour la vie. Their story touched me so much… I felt exactly the same pain. I then decided to write to them. Stéphane, whom I particularly welcome, quickly answered me and directed me to the best specialists in order to have another opinion. At the same time, Eva pour la vie provided me with financial assistance to support Y.'s treatment (Rapamune, 2mg). In full confinement, the association allowed us to benefit from free accommodation near the hospital where our daughter was being cared for, because the parents' houses were closed. What Eva pour la vie did is just enormous because thanks to them, other children and patients with other pathologies were able to be accommodated during this difficult period of covid19 and thus continue their care. A big thank you to this association of great values which does a lot to help pediatric cancer research and which also helps to soften, help and support all families in distress.

Family of Mathys, 8 years old
Following the announcement of the disease of our little warrior (neuroblastoma) we had to stop working to ensure hospitalizations and all that goes with it. As a result, over time financial problems arose and we were no longer able to cope with the invoices (Edf, taxes, etc.). It was then that we appealed to the Eva pour la Vie association, while our bank was not supporting us in this ordeal. Thanks to the association, we were able to pay our bills, bring our account up to date and negotiate together with the bank, which then agreed to reimburse part of the fees it took from us every month. Thanks to Eva pour la vie our life has changed a lot. We can devote ourselves to our warrior and the financial problems are behind us.

Family of Laura, 14 years old
Laura fell ill three and a half years ago, and relapsed from leukemia in March 2020. She was treated in several hospitals and had a transplant. She is still hospitalized. The association has helped us greatly. Fortunately, it exists, it is essential. We received wise and relevant advice, significant financial assistance, contacts with other organizations […]. The association also gives us moral support, and we know that we can count on it in case of problems or various questions. The association found us accommodation near the hospital, following the problems encountered with the parents' house (an organization which normally has to house the parents of sick children).

 

• November 2018: 5 million euros per year earmarked for basic research in pediatric oncology.The use of this allocation, which is complementary to existing general funding, is decided in conjunction with the representatives of the associations. The National Cancer Institute is in charge of coordinating the action plan. This decision was taken after several amendments (Jean-Christophe Lagarde, Benoit Simian, Eric Woerth, etc.) debated in the hemicycle at our instigation. The deputies Amélie de Montchalin, Benoit Simian and Laurianne Rossi as well as the Minister of Research Frédérique Vidal enabled the implementation of this progress.
  https://www.gouvernement.fr/cancer-de-l-enfant-5-millions-d-euros-de-plus-par-an-pour-la-recherche-fondamentale
  
  
  
• May 2020: Guy Bricout's bill (taken over and enriched by the government) aimed at supporting families after the death of a child (known as the "mourning law"). She understands :
  - Bereavement leave increased from 5 to 15 split days
  - The maintenance of social aid (CAF etc.) in connection with the child for 3 months. Until now, aid stopped immediately after the death of a child. An improvement has also been made for RSA beneficiaries.
  - The creation of a public death benefit, which will cover funeral expenses, automatically paid to all families of deceased children by CAF, in accordance with the proposals made by Eva pour la vie and the work carried out with MP Sereine Mauborgne, François Ruffin...
  - Protection of bereaved families against dismissal for a period of 13 weeks
  - Reimbursement of psychological support (urban psychologists, etc.)
  https://www.caf.fr/allocataires/aides-et-demarches/ma-situation/accident-de-vie/mon-enfant-est-decede
  
  
  
• November 2020: Doubling of the duration of the AJPP.
  This bill was carried by the deputy Paul Christophe adopted. After raising their awareness, we carried out a complete assessment of the situation, testimonials from families to justify the usefulness of this measure, which should also ultimately lead to the implementation of broader social measures to families of sick children, victims of life accidents, who have to reduce or even cease their professional activity for this reason.
  https://www.assemblee-nationale.fr/dyn/15/textes/l15b3422_proposition-loi
  
  
  
• October 2021: vote of an additional 20 million euros for research on pediatric cancers
  As we demonstrated in a report, the earmarking of €5M/year allocated since the end of 2018 showed both its effectiveness and its limits, due to a constrained budget. Supported by deputies LR, LFI but also by the majority (in particular, Puerre Cabaré, who intervened in a very strong way), the amendment of the deputy for the North Béatrice Descamps voted in the PLS2022, allows an acceleration of this work as well as an improvement in the structure
  https://www.evapourlavie.com/recherche-sur-les-cancers-pediatriques-amendement-20-millions-beatrice-descamps.html
• December 2021: Law aimed at supporting children with chronic illnesses or cancer
  This bill drafted by the deputy of the North Béatrice Descamps creates a specific leave of 2 days when announcing a cancer or a chronic pathology in the child. It will also make it possible to better secure the course of the pupils concerned by such situations.
  https://www.senat.fr/dossier-legislatif/ppl20-490.html 
  
  
  
• January 2022: revaluation of the AJPP to the SMIC
  This progress, obtained thanks to the intervention of the deputy Paul Christophe, was part of our demands included in our petition. On average, the full-time AJPP – open to any parent having to cease their professional activity to accompany their seriously ill child – therefore goes from 900 to more than 1300 euros.
  https://www.legifrance.gouv.fr/jorf/id/JORFTEXT000045084510
  
  
  
• July 2023: vote on a law aimed at strengthening the protection of families of children suffering from an illness or disability or victims of a particularly serious accident.
  This bill co-constructed by MP Paul Christophe and Eva pour la vie was voted on and applied in just 5 months, with support involving cross-party parliamentarians. It aims to:
  - Protect parents from dismissal when they have to reduce or stop their professional activity to support their child,
  - Extend the leave for the announcement of a serious pathology of a child from 2 days to 5 days,
  - Extend bereavement leave to 14 days for the death of a child under 25 and to 12 days regardless of age,
  - Facilitate access to teleworking for these same parents,
  - Simplify the procedures for renewing the Daily Parental Presence Allowance (#ajpp) by removing the condition of an explicit prior agreement from the medical control department and allowing the CAF to pay an advance to the beneficiaries within 15 days,
  - Remove the AJPP and AJPA capping measure paid to non-employees in agricultural professions not affiliated to pension insurance, to their collaborating spouses and partners and to non-employees in agricultural professions ceasing their activities ,
  - Protect these families from breaking the lease when they are tenants,
  - Better support parents by experimenting with improvements with the CAF.
  https://www.legifrance.gouv.fr/jorf/id/JORFTEXT000047862209  

Dr Olivia Fromigue's team has identified the MT2A protein, the presence of which is essential for osteosarcoma cells to survive in the face of chemotherapy. Analysis of tumor samples taken before the start of chemotherapy revealed that if the tumors express little MT2A, patients will respond well to treatment, whereas if the MT2A level is already high, patients will be poor responders with a reduced survival rate. Thus, their work suggests that MT2A would be a predictive marker of resistance to chemotherapy which can be used from diagnosis.

The next question was to consider using MT2A as a therapeutic target. They have just provided proof of concept that blocking the expression of MT2A significantly improves the effect of chemotherapy in vitro and in animals. Before considering a clinical development of this discovery, it is necessary to fully characterize the roles of MT2A in the whole tumor and not only in the tumor cell. Their current project, financially supported by Eva pour la vie (through a grant of 21,000 euros, paid in early 2020), aims to study the role of MT2A in communication between tumor cells and the body's defense cells. Indeed, the team suspects her of participating in the tolerance of tumors by the immune system ...


Interview with Dr Olivia Fromigue

Why did you decide to do research on childhood cancer?
Research on childhood and adolescent cancers is essential, alongside adults because the biology is very different. And certainly more so for growing bone tissue. I had already noted and studied it during my thesis: the functioning and the activity of a formative bone cell are different in the fetus, the child, the adult and the elderly. The response of tumor cells to treatments defined for adults is also different. It is essential to better understand, to characterize in detail the tumors of the child in order to propose perfectly adapted therapeutic solutions. Our work aims to understand how tumor cells cope with anticancer drugs - mainly chemotherapy - and why some tumors are not sensitive to them and resist treatment.

 

Why are you interested in osteosarcoma?
During my thesis, I studied the mechanism of bone formation in adults and children. Then I went on a post-doctoral position at the tumor center of the Université Libre de Bruxelles, in a team working on metastatic breast cancer and which wanted to set up a research project on the interactions between mammary tumor cells and bone cells. . I was then their referent for normal bone tissue and I learned a lot about the deregulations and dysfunctions that exist in tumor cells. Then, I did a second post-doctorate in Nice on the theme of communication between tumor cells and normal cells (in the lung cancer model) while training myself in a technique then in full swing: DNA chips. It is clear that the different cells communicate a lot. Normal cells receive signals from tumor cells and will adapt their behavior unfortunately very often to “serve” and “benefit” from the development of the tumor. Back in the Paris region, I focused my projects on bone cancer, especially since at the time little research was carried out on this rare cancer. I then had the chance to join the Gustave Roussy Institute and to interact with other researchers and especially clinicians aware of bone tumors, and therefore to be as close as possible to clinical reality.

Could this project lead to cross-cutting advances, that is to say beyond osteosarcoma, for children?
Yes, our work is carried out in the osteosarcoma model, but the MT2A protein can be produced by any normal cell in the body which has to face chemical or toxic aggression. The same may be true for tumor cells. The link between the level of expression of MT2A by the tumor and the prognosis has moreover been described in the literature in cases of breast, stomach and prostate cancer, etc. On the other hand, there is no data. was still available as to the role of MT2A in pediatric cancer.

 

Why is funding from Eva for Life, and associations, important to you?
While funding from major national (or even international) programs is very rigid, ad hoc support from associations is decisive for initiating research projects, providing the preliminary results that are essential to convince major funders. This also makes it possible to quickly reorient the work towards promising lines of research.

Dr Max Piffoux, you are both a medical student and a post-doctoral researcher at INSERM at INSERM in Lyon. You have decided to focus your research on osteosarcomas in children. Can you tell us more about this project, and your motivations for working on childhood cancer? Was it difficult to convince your team?
First of all, I want to clarify that I am not alone in leading this project, it is a team story! The origin of the project is above all a story of meetings, of shared enthusiasm, like many research stories. We have developed this project to confirm the interest of a new type of molecules to potentiate the effect of immunotherapies. They have the advantage of not having any side effects a priori, of being easy to administer by mouth. They have not yet been developed by drug manufacturers, but if this were the case they could quickly end up in clinical trials. At the start of this project, we were looking for a cancer model resistant to immunotherapy to confirm results obtained in other sarcomas. Among the cancers resistant to immunotherapy, osteosarcomas are particularly resistant, and affect a predominantly pediatric population. I was also made aware of the subject by my partner, a resident in pediatric orthopedic surgery and co-sponsor of the project. We are also working with a Parisian team specializing in this type of molecules. This made me understand that this pathology was particularly relevant from a scientific but also a medical point of view: resistance to immunotherapies, few therapeutic avenues, no change in care for 30 years ... unfortunately it is an area where there is still work to be done, a real challenge. I hope we can add a stone to the edifice.


What is the current therapeutic situation, and what are your hopes?
In osteosarcoma, treatment is currently based on surgery and chemotherapy. It is a very cumbersome protocol, but it works relatively well for some patients. If unfortunately patients do not respond or relapse, treatment options are very limited. I think that therapeutic innovation in the field will come either from the addition of molecules without side effects to the current treatment, or from new second-line approaches which, if they prove to be effective, could perhaps replace the first line. We see that in the second case the road is long. Instead, we chose to focus on the first option: developing non-toxic treatments in combination with the current treatment. We know that our "drug candidates" have shown their efficacy in another type of sarcoma resistant to immunotherapies, making it sensitive to immunotherapies when combined with chemotherapies, in particular those used for osteosarcomas. Our goal, if the results are promising in animals, is to set up a trial to test these molecules directly on the front line. However, we know that it takes a long time for a new treatment to arrive in a clinical trial, especially for these pathologies with few patients.


Do you plan to develop this project with other researchers and extend it to other types of pediatric cancers?
Of course ! More generally, we target cancers resistant to immunotherapy, including certain pediatric ones such as Ewing's sarcoma or neuroblastoma. The project is already made up of a team of researchers, but the door is intended to remain open.


Did you encounter any financial or administrative difficulties in launching this project? What does the financial support of Eva for Life and Aidons Marina allow you to do?
I must admit that since I arrived in Lyon a year and a half ago, I have been welcomed with open arms by the teams of the Center Léon Bérard. From a financial point of view, everything went well because the support of Eva for life and Aidons Marina was very quick to obtain! I think we underestimate the role of this kind of preliminary funding for young researchers, who spend their time looking for money at the expense of time spent doing research ... This will allow us, if the results are conclusive, to find funding to take this project further.


In addition to collecting donations, Eva pour la vie has launched a fundamental initiative aimed at encouraging the State to create a fund dedicated to research on childhood cancer, as well as to improve aid to families of children. sick children. A first victory, undoubtedly insufficient but unprecedented, was obtained at the end of 2018: the vote of a fund of 5 million euros / year for this research. What do you think ?
I think research in general needs support. The share of French GDP devoted to research, both public and private, is low compared to other comparable countries. Seen from inside the public system, researchers are paid to spend about 25 to 50% of their time looking for money to work. The creation of this fund is a great step forward!


What would you like to say to families whose children are battling cancer?
This is a more than difficult question! Wish them courage of course, but also thank them for their help. The research is unfortunately relatively slow, we put all our heart into it. Quick financial support like the one you give allows new avenues of research to emerge quickly.

Today, conventional chemotherapy cannot cure the majority of common cancers. Most of the drugs used clinically have little selectivity towards tumor cells and also attack healthy tissue. This non-selective destruction causes severe side effects and often leads to premature discontinuation of treatment.

Recent studies have highlighted some malignant specificities which make it possible to differentiate tumors from healthy tissues. The discovery of these potential targets has led to the development of several therapeutic targeting systems. The objective of these new strategies (vectorized chemotherapies) is to convey a drug to its site of action using a non-toxic vector, then to regenerate its anticancer activity exclusively at the level of the tumor. This approach has several advantages over conventional chemotherapy. Indeed, the selective localization of the cytotoxic molecule in the area to be treated limits the side effects observed during its systemic administration. In addition, the low toxicity of the vector makes it possible to increase the quantity of active agent administered in the organism and thus its concentration at the level of the tumor in order to lead to a more effective treatment.

In this context, the team of Professor Sébastien Papot based at the Poitiers Institute of Chemistry of Media and Materials, has developed new molecules capable of selectively destroying many human tumors (breast, colon, lung, pancreas, head and neck) implanted in mice without causing side effects in animals. Unprecedented results have been obtained in particular for the treatment of pancreatic tumors, a pathology for which there is currently very little therapeutic solution.

Thanks to a collaboration with the team of Doctor Christophe Grosset (INSERM U1035, Bordeaux) and the support of the Eva pour la Vie association, this new therapeutic concept is now being evaluated for the treatment of childhood tumors.

November 2019 update : Click here to read the summary & visuals

Dr Patrick Auguste you are in charge of the study of Wilms tumor in the MiRCaDe team led by Dr Christophe Grosset. Can you tell us more about the project and the motivations that led you to work on childhood cancer?

For more than 20 years I have been working on cancer, more specifically in adults. And it's been almost 10 years since I went to kidney cancer or renal cell carcinoma. By joining the team of Dr Christophe Grosset (Inserm unit 1035, MiRCaDe team), I wanted to climb a new level in my career and work on childhood cancer without however moving away from what I knew, it is ie renal carcinoma. I remain convinced that the treatments for cancer in children must be completely different from those in adults. For that we must find new targets for these treatments, and we must therefore understand how childhood cancers and in particular, in my case, how nephroblastoma or Wilms tumor develops.

Wilms tumor is the main kidney tumor in children. It develops from the developing kidney and affects 1 in 100,000 children, which represents 100 cases per year in France. It is generally well cared for but in a little less than 10% of cases it results in the death of the patient mainly because of metastases. 10% of patients, it doesn't seem like much, but it's still too much for young children. In addition, chemotherapy and, possibly, radiotherapy are heavy for a young child and can be disabling afterwards.

The aim of the project is to characterize other therapeutic targets in high-risk Wilms tumors, ie tumors that can lead to the death of the child. For this we will identify the proteins that are specifically present in high risk tumors and which are absent in lower risk tumors. These proteins, present only in high-risk tumors, could subsequently be studied and targeted in new therapies.

Did you encounter any technical difficulties in launching this project?

The main difficulties lie in the study of future target proteins. For this, it is absolutely necessary to start studying them in the laboratory on Wilms tumor cells. However, there is only one commercially accessible cell line. This very certainly reflects a great difficulty in obtaining cells in culture from tumors. It is therefore proposed to obtain new cell lines from tumors. For this a technique recently used with success for obtaining a new Wilms tumor line will be used. So our project will also be used to obtain cell models which will then be accessible to the scientific community.

The characterization of the proteins specifically expressed in high-risk Wilms tumors will be carried out by a new technology developed at the University of Bordeaux by Dr Anne-Aurélie Raymond and Fréderic Saltel. Wilms tumors, like many pediatric cancers, are rare tumors and very often laboratories only have blocks of tumors that have been firmly fixed for the pathologist to make a diagnosis. The problem with binding is that it modifies the proteins and that it is subsequently impossible to characterize them. In this new technique, changes in proteins due to binding are reversed and it is subsequently easy to identify the proteins by a method called mass spectrometry. Once these proteins are identified, with the help of cultured cells, we can study the role of these proteins in high risk Wilms tumors. The aim, of course, is then to be able to inhibit the activity of these proteins in order to be able to kill the cells and therefore destroy the tumor.

Can you introduce us to the team that will work with you on the project?

I am part of an Inserm unit in Bordeaux (U1035), headed by Dr Alain Taïeb, who works on cancer mainly in adults. This unit is divided into several teams, including the MiRCaDe team to which I belong. This team, led by Dr Christophe Grosset, works mainly on pediatric cancers and more particularly on hepatoblastoma, infiltrating glioma of the brainstem and, now, Wilms tumor. The Wilms tumor project is international and will bring together people with different and complementary specialties. It will bring together, in addition to myself, a doctoral student from the University of Bordeaux and the team that developed the technique for identifying proteins. It will also be done in collaboration with a team of doctors in Seville (Spain), more particularly by Drs de Alava and Ramirez-Villar. Dr de Alava is the pathologist who monitors all kidney cancer diagnoses in Spain and Dr Ramirez-Villar is a member of the European Committee for Childhood Kidney Cancer (SIOP RTSG), a committee that defines the treatment of all pediatric cancers of the kidney. They are the ones who will provide the tumor blocks, the cells to be cultured and who will participate in the characterization of the role of the proteins characterized in high-risk tumors.

Did you encounter any financial or administrative difficulties in launching this project? What will Eva's financial support for life allow you to do?

In all projects, including this one, the hardest part is finding the money to start. The risks are higher when starting a project compared to an already established project. But it is also the risks that lead to new discoveries. The funding provided by Eva for Life will allow us to finance the characterization of proteins in high risk tumors. It is therefore highly crucial and will allow us to characterize proteins that can serve as therapeutic targets in order to treat high-risk Wilms tumors.

Dr Fabienne Meggetto, you are research director at INSERM Toulouse. You have decided to focus your research on lymphomas in children. Can you tell us more about this project, and your motivations for working on childhood cancer?

Lymphoma is cancer that affects cells of the immune system, i.e. lymphocytes. Lymphocytes are white blood cells that help the body fight infections. They are made in the bone marrow, spleen, and lymph nodes, and then travel through blood and lymph vessels. Their mission is to identify and fight infections and abnormal cells. There are two main types of lymphocytes: B lymphocytes and T lymphocytes. Lymphoma occurs when abnormal / mutated B or T lymphocytes have grown out of control. The abnormal lymphocytes multiply in abnormal ways and as they accumulate, they eventually form tumors, especially in the lymph nodes. But as lymphocytes circulate throughout the body, they can affect many other organs as well. Lymphoma falls into two broad categories: Hodgkin lymphoma and non-Hodgkin lymphoma. In children under 15, the most common type of lymphoma is "non-Hodgkin's". These are the 3 ^rd cause of cancer in children after leukemia and brain tumors.

Anaplastic large cell lymphomas are aggressive non-Hodgkin lymphomas that affect T lymphocytes. Anaplastic large cell lymphomas, although rare, represent 15% of non-Hodgkin lymphomas in children and young adults, which makes them lymphomas. most common pediatric patients. In children, 90% of anaplastic large cell lymphomas are associated with a chromosomal translocation which results in the expression of an abnormal protein, NPM-ALK. Although NPM-ALK (+) anaplastic large cell lymphomas are relatively sensitive to chemotherapy, about 30% of young patients relapse early and these relapses have poor prognosis. The search for biomarkers of early relapses is therefore essential for this pediatric cancer.

MicroRNAs are part of the family of molecules called non-coding RNA. They form one of the major pathways for regulating gene expression. Our group is one of the first to have demonstrated in anaplastic large cell lymphomas NPM-ALK (+), microRNAs as tissue biomarkers of resistance to treatment. MicroRNAs are found in tumor cells and can be secreted into circulating body fluids such as blood. However, it has been reported that only 10% of known human microRNAs can be detected in plasma and around 30% of these are poorly represented forms. Our project is interested in other non-coding RNAs, circular RNAs, which are abundant, stable, very resistant molecules and which have been validated as serum biomarkers in solid tumors. Our main objective is therefore to identify serum circRNAs associated with failure / resistance to treatment of anaplastic large cell NPM-ALK (+) lymphomas in children.

 

What is the current therapeutic situation, and what are your hopes?

The standard treatment for pediatric anaplastic large cell lymphoma is a combination chemotherapy different from that used to treat anaplastic large cell lymphoma in adults. Although NPM-ALK (+) anaplastic large cell lymphomas are relatively sensitive to chemotherapy with high response rates, event-free survival is still between 65 and 75% in children. Thus about 30% of young patients relapses early and these relapses are always poor prognosis. Different targeted therapies, that is to say therapies directed specifically against tumor cells have already been tested for the management of chemo-resistant forms of anaplastic large cell lymphomas NPM-ALK (+) in children, such as therapy by antibodies, anti-ALK inhibitors, the leader being crizotinib, and more recently immunotherapy. These drugs are developed to block the growth or spread of tumor cells by acting on particular alterations that cause the development or spread of tumor cells. This so-called “targeted” action makes it possible to act more specifically on tumor cells and thus limit the damage suffered by normal cells. However, due to adverse reactions associated with treatment with certain antibodies, cases of sudden relapses following discontinuation of crizotinib, and no continued clinical remission after discontinuation of Crizotinib in other cases, clinicians are at an impasse therapeutic if a bone marrow transplant is not possible. The search for biomarkers of early relapses is therefore essential.

 

Do you plan to develop this project with other researchers - including internationally - and extend it to other types of pediatric cancers?

Prof. Laurence Lamant, referring pathologist for anaplastic large cell lymphomas (pathology department, Toulouse University Hospital, IUCT-Oncopole) and member of my group is historically involved in the morphological, genetic and molecular characterization of anaplastic large cell lymphomas. . She is a member of an interdisciplinary working group within the lymphoma committee of the French Society for Cancer in Children and Adolescents (SFCE). At the same time, we have long had collaborations with European and international cooperative groups active in childhood lymphoma. It also encourages interactions with the Adult Lymphoma Cooperative Group (Adult LYSA). Very soon a German pediatric neuro-oncopediatrician will join my group for two years. He will be 100% involved in the project and through his training we plan to extend our project to other pediatric cancers, in particular neuroblastoma . In fact, a mutation of the ALK gene has been described in approximately 12% of cases of neuroblastoma in children, which is the most frequent extracerebral solid malignancy in young children.

 

Did you encounter any financial or administrative difficulties in launching this project? What will Eva pour la vie's financial support allow you to do?

The financial support that I receive from the Eva pour la vie association is essential for the start of the new research project that I want to develop. Without this support, after several refusals, the project could not see the light of day for lack of funding. The money entrusted to me will allow me to carry out experiments essential to the start of the project and therefore to generate the first data. This step is essential for projecting the project towards a translational study with the clinic.

 

Eva pour la vie launched a fundraising initiative - now followed by numerous associations - aimed at encouraging the State to create a fund dedicated to research on childhood cancer, as well as to improve support for families. of sick children. With a first victory, undoubtedly insufficient but without precedent: the vote, at the end of 2018, of a new fund of 5 million euros / year for this research. What do you think ?

I “donf” support the motivation of the Eva Pour La Vie association and the Growing Up Without Cancer Federation because the absence of national calls for tenders specific to pediatric cancers is an aberration. Indeed even if certain cancers are observed at the same time in children and adults, they present their own specificities. It is therefore essential to be able to study / compare them in order to better characterize them in their biology and their responses to treatments. This in order to allow a better diagnosis, prognosis and to broaden the therapeutic options. But one of the engines of medical research remains the financial profits for the private industry often also involved in the financing of clinical trials. Childhood cancers being rare diseases and therefore a weak economic market, it is therefore somewhat interesting compared to adult cancers (lung cancer, breast, etc.). The state must compensate for this by ensuring the funding of research work without necessarily immediate financial benefits but advances in public health, such as the improvement of the prognosis, diagnosis of the care of patients and their families.


Scientific publication (November 2020)
T cells transformed in the laboratory help to better understand the origin of childhood lymphoma.
https://insb.cnrs.fr/fr/cnrsinfo/des-lymphocytes-t-transformes-en-laboratoire-aident-mieux-comprendre-l origin-dun-lymphome

The Journal of National Cancer Institute published in June 2022 a study conducted in Denmark based on cancer and drug consumption registers. A 20-year follow-up highlights a risk multiplied by 3 of osteosarcomas and by 2 of Hodgkin's and non-Hodgkin's lymphomas in the event of exposure via drugs using DEP phthalate (DiEthyl Phthalate) in gastro-resistant drugs. The risk is statistically significant at the 95% level.

The transposition to the French reality on a purely demographic level (270 cases over 20 years) gives an order of magnitude but should not be taken literally, due to the lack of comparison on the specific consumption of each country.

It seems plausible that contamination of children and adolescents via environmental sources (mainly personal care products) could have played a role.

The scientific literature also clearly highlights the fact that DEP cannot be considered as a neutral excipient. It interacts with other phthalates and even with other families of Endocrine Disruptors, such as perfluorides in the genesis of childhood diseases. It also more specifically impacts osteoblasts.

The results suggest that this phthalate should be eliminated from consumer products and in priority from medicines. The recent roadmap of the European Commission on chemical products has provided for the elimination of major families of endocrine disruptors such as phthalates.

References :

Sarah Bachir "Childhood cancers, phthalates and drugs" Internship dissertation for the 5th year of Pharmacy Industry and Research - Toxicology specialty. Faculty of Pharmacy of Paris.

Thomas P Ahern, Logan G Spector, Per Damkier, Buket Öztürk Esen, Sinna P Ulrichsen, Katrine Eriksen, Timothy L Lash, Henrik Toft Sørensen, Deirdre P Cronin-Fenton. Medication-Associated Phthalate Exposure and Childhood Cancer Incidence J Natl Cancer Inst. 2022 Jun 13;114(6):885-894. doi: 10.1093/jnci/djac045

Sarah Bachir's internship carried out at the Health Environment Network from April to August 2022. Internship supervisor André Cicolella.

- La mise en place d'une vraie politique publique du développement de médicaments pédiatriques, tout particulièrement pour les cancers et maladies graves de l'enfant.

A ce jour, ceux-ci sont généralement considérés comme un "marché restreint, trop peu rentable". Les traitements existants reposent essentiellement sur la "chance" qu'ils aient d'abord été développés pour l'adulte, pour être ensuite (parfois, des années après) adaptées à l'enfant. Sur les 15 dernières années, AUCUN médicament n'a été développé en 1ère intention pour les enfants atteints de cancers de mauvais pronostic. Seuls 16 médicaments anticancéreux - tous initialement développés pour l'adulte - ont été autorisés pour une indication spécifique de cancer pédiatrique, contre plus de 150 pour les cancers de l’adulte.
Malheureusement, la plupart ne concernaient le traitement de tumeurs malignes responsables de moins de 4 % de tous les décès par cancer chez les enfants en Europe, y compris trois médicaments pour le mélanome et le cancer de la thyroïde – des cancers d’adultes qui se produisent très rarement chez les enfants. 

Conséquence logique : l'impact sur le taux de survie des enfants a été quasiment-nul, ce qui n'a pas empêché, à travers le réglement pédiatrique européen de 2006, les grands industriels de bénéficier d'un certain nombre de récompenses. Pour certaines maladies spécifiquement pédiatriques - telles que les tumeurs du tronc cérébral, qui emportent tous les enfants touchés - il est indispensable de développer des traitements pédiatriques en première intention, en exploitant les découvertes issues de la recherche (mieux financée par l'Etat depuis 2018, mais qui ne sert à rien si elle n'est pas exploitée au niveau thérapeutique ou préventif) et en menant une politique nationale volontaire sur ce sujet.

- La mise en place d'une vraie politique publique de prévention des cancers et maladies pédiatriques, avec la mise en place d'un principe de précaution dès lors que les publications scientifiques évoquent une suspicion importante pour l'enfant ou la femme enceinte. C'est par exemple le cas pour les pesticides.

- La recherche systématique des causes et origines des cancers pédiatriques, dès lors qu'une cause n'est pas connue, à travers des prélèvements biologiques et environnementaux et des questionnaires à l'ensemble des parents concernés. 

- L'alignement de l'AJPP (allocation journalière de présence parentale) et de l'AEEH (allocation d'éducation de l'enfant handicapé), tant en termes de délai (sous 2 mois maximum) que de montant (revalorisation au SMIC) pour tout parent contraint, au vu de la gravité de l'état de santé ou handicap de son enfant, de cesser totalement son activité professionnelle. En parallèle, l'accompagnement et la lutte contre la fraude sociale seraient renforcées.

- Le remboursement des thérapies scientifiquement reconnues, tant en France qu'à l'étranger, aussi bien pour le handicap que pour les cancers et maladies graves, dès lors qu'elle est prescrite par un médecin pour permettre l'amélioration de l'état de l'enfant ou de ses chances de survie. Objectif : aboutir à un 0 reste à charge réel, afin d'assurer une égalité des chances pour tous ces enfants, quels que soient les revenus du parent, et aussi, lutter contre le charlatanisme.

- La prise en charge du logement près de l'hôpital (maison des parents ou si non disponible, logement privé) pour tous les parents devant accompagner durablement leur enfant atteint d'un cancer ou d'une maladie grave nécessitant une hospitalisation prolongée. Certains services ne disposent pas d'un lit accompagnant. De plus, il est parfois nécessaire que les 2 parents soient présents, voire toute la famille, notamment face aux situations les plus graves. 

- L'amélioration, dans la continuité de la loi de Paul Christophe votée en 2023, de la protection des familles face au crédit immobilier, à l'administration fiscale ou à l'école. Mise en place de mesures visant à soulager les familles des démarches administratives : simplification du processus d'attribution d'une carte stationnement handicapé, qui pourrait se faire directement par le biais de l'hôpital lorsque cela concerne un enfant gravement malade, accélération des délais ... la notion d'une meilleure reconnaissance des assistantes sociales et des professionnels soignants fait également partie de nos objectifs.

- L'amélioration des conditions d'accueil et de traitement des enfants hospitalisés, à travers la mise en place de moyens financiers adaptés (pour l'accueil et l'alimentation, très inégaux d'un service à l'autre) et d'audits associant parlementaires, médecins, associations et familles.

- L'amélioration de la politique du don de vie (don de sang, de moelle osseuse, de plaquettes…), en commençant par les écoles en incluant ces notions à l’apprentissage scolaire, du primaire jusqu’au lycée ou même l'enseignement supérieur. Des heures de cours en lien avec la santé pourraient être dispensées par les enseignants, les associations spécialisées et les professionnels de santé. Nous proposons également un ensemble de leviers à destination des salariés des entreprises & administrations françaises.

Lire aussi : les droits & avancées légales obtenues

Vous avez décidé d’orienter vos travaux de recherche sur les cancers de l’enfant. Pouvez-vous nous en dire plus sur vos motivations à travailler sur les cancers de l’enfant ?

J'ai choisi de diriger mes travaux de recherche vers les cancers de l'enfant en grande partie grâce à une expérience personnelle. Lors d'une conversation avec mon fils à propos de la maladie de son amie, j'ai été interpellé par ses questions d'enfant sur les cancers. Il m'a demandé si je travaillais sur les cancers, et j'ai répondu par l'affirmative, expliquant que je cherchais de nouveaux traitements pour les guérir. Cependant, il m'a alors demandé pourquoi je ne travaillais pas spécifiquement sur les cancers des enfants.

C'est à ce moment précis que mon fils m'a annoncé que l'une de ses amies, Imene, était atteinte d'un cancer, et qu'il espérait que je puisse travailler sur ce type de cancer pour la sauver. Cette conversation a profondément touché mon cœur et m'a incité à prendre la décision de me concentrer sur la recherche des cancers pédiatriques. Par une heureuse coïncidence, au même moment, j'avais également pris la décision de partager mon laboratoire avec l'équipe du Dr. Birgit Geoerger, pédiatre à Gustave Roussy.

En outre, après avoir discuté avec des chercheurs pédiatres de Gustave Roussy et de l'Institut Curie, il est devenu évident qu'il existait un besoin pressant de développer de nouveaux traitements pour les cancers pédiatriques. Cette convergence d'éléments personnels et professionnels a renforcé ma détermination à consacrer mes efforts à la recherche sur les cancers de l'enfant et à contribuer à améliorer les perspectives de guérison pour ces jeunes patients.

Plus précisément, pouvez-vous nous en dire plus sur votre projet soutenu par Eva pour la vie ? Sur quels types de cancers porte-t-il ? Quels sont vos espoirs au niveau thérapeutique ?

Notre projet, soutenu par Eva pour la vie, est axé sur l'identification de nouvelles molécules immunomodulatrices. Ces molécules sont capables d'induire des réponses immunitaires spécifiques contre les cellules cancéreuses. En d'autres termes, nous travaillons sur des substances qui ont la capacité de stimuler les cellules cancéreuses à produire des peptides antigéniques. Ces peptides peuvent ensuite être reconnus de manière spécifique par les cellules lymphocytaires du système immunitaire, ce qui entraîne leur multiplication et leur capacité à détruire les cellules cancéreuses.

Notre projet de recherche se concentre sur plusieurs types de cancers pédiatriques, notamment le neuroblastome, l'ostéosarcome et le glioblastome. Ces cancers sont particulièrement graves et nécessitent des approches thérapeutiques novatrices.

Nous avons commencé notre projet il y a environ un an, et nous avons déjà obtenu des résultats préliminaires prometteurs avec certaines de nos molécules immunomodulatrices. Notre objectif ultime est de protéger ces molécules par le biais de brevets spécifiques aux cancers pédiatriques, ce qui pourrait ouvrir la voie à de nouvelles options de traitement pour les enfants atteints de ces types de cancer.

Nos espoirs au niveau thérapeutique sont de développer des traitements plus efficaces et ciblés pour ces cancers pédiatriques graves, en exploitant le potentiel du système immunitaire pour lutter contre les cellules cancéreuses. Nous aspirons à améliorer les perspectives de guérison et la qualité de vie des enfants atteints de ces maladies dévastatrices.

Envisagez-vous de développer ce projet avec d’autres chercheurs - y compris à l’échelle internationale – et l’étendre à d’autres types de cancers pédiatriques ?

Nous sommes en cours de discussion avec l'Institut RECAMO à Brno, en République tchèque, pour évaluer l'effet de nos molécules immunomodulatrices sur le glioblastome. Ce projet vise à utiliser nos molécules sur des organoïdes de glioblastome et à analyser leur effet immunomodulateur sur ce type spécifique de tumeur. Les organoïdes de glioblastome sont des modèles de tumeurs qui sont capables de reproduire fidèlement les caractéristiques génétiques, histologiques et morphologiques de chaque tumeur.

Cette collaboration avec l'Institut RECAMO démontre notre volonté de développer notre projet en partenariat avec d'autres chercheurs, y compris à l'échelle internationale. Nous sommes ouverts à l'idée d'étendre nos recherches à d'autres types de cancers pédiatriques ou à d'autres partenariats de recherche pour contribuer à la lutte contre le cancer chez les enfants.

Avez-vous rencontré des difficultés, financières ou administratives, pour lancer ce projet ?  Qu’est-ce que le soutien financier d’Eva pour la vie, vous permet de faire ?

Nous n'avons pas rencontré de difficultés majeures pour lancer notre projet, en grande partie grâce à une collaboration étroite avec le professeur Birgit Geoerger, un chercheur pédiatre à Gustave Roussy. De plus, nous avons bénéficié d'un financement de l'INCa six mois avant de recevoir le soutien financier d'Eva pour la vie. Ce financement initial de l'INCa nous a permis d'embaucher une ingénieure de recherche, ce qui a été une étape cruciale pour mettre en place notre projet.

Pour autant, le soutien financier d'Eva pour la vie a eu un impact significatif sur nos activités. Grâce à ces fonds, nous avons pu entreprendre la sélection des molécules potentiellement immunomodulatrices pour le traitement des cancers pédiatriques parmi nos différentes molecules. De plus, nous avons commencé à mener des études in vivo sur des modèles murins de cancer pédiatrique, ce qui représente une étape importante dans notre recherche visant à développer de nouvelles thérapies.

 

Au-delà de l’appel à la générosité publique, Eva pour la vie a impulsé dès 2012 une démarche inédite en Europe – désormais partagée par de nombreuses associations à travers la fédération Grandir Sans Cancer – demandant à l’Etat à créer un fonds dédié à la recherche sur les cancers de l’enfant, ainsi qu’à améliorer l’aide aux familles d’enfants malades. Avec Grandir Sans Cancer, elle a obtenu fin 2018 le vote d’un fonds annuel dédié de 5 millions d’euros/an pour cette recherche, et fin 2021, de 20 millions d’euros supplémentaires. Que pensez-vous de cette mobilisation ?

Je pense que la mobilisation d'Eva pour la vie et de la fédération Grandir Sans Cancer pour la recherche sur les cancers de l'enfant est extrêmement louable et importante. La lutte contre le cancer chez les enfants est un enjeu crucial de santé publique, et il est essentiel de mobiliser des ressources pour soutenir la recherche et améliorer le soutien aux familles d'enfants malades.

La création d'un fonds dédié à la recherche sur les cancers de l'enfant montre une prise de conscience de l'importance de cette cause. L'obtention de financements substantiels est une avancée significative. Ces ressources financières ont déjà permis et vont permettre de financer une recherche fondamentale nécessaire pour mieux comprendre les cancers pédiatriques, développer de nouvelles thérapies et pour améliorer les taux de survie.

De plus, l'amélioration de l'aide aux familles d'enfants malades est tout aussi cruciale. Faire face à un diagnostic de cancer chez un enfant est une épreuve extrêmement difficile pour les familles, et elles ont besoin de soutien émotionnel, financier et logistique pour traverser cette période difficile. La mobilisation en faveur de ces familles est un aspect important de la lutte contre le cancer chez les enfants.

Je pense donc que la mobilisation d'Eva pour la vie et de la fédération Grandir Sans Cancer est admirable, nécessaire, et les fonds alloués à la recherche et à l'aide aux familles sont une étape importante vers une meilleure prise en charge des enfants atteints de cancer en France et en Europe.

Publications scientifiques : en savoir plus 

Dr Thierry Virolle, vous êtes Directeur de Recherche INSERM. Vos travaux portent notamment sur les glioblastomes, un cancer agressif pouvant affecter l’adulte mais aussi l’enfant. Pouvez-vous nous en dire plus sur vos motivations à travailler sur les tumeurs cérébrales pédiatriques ?

Depuis une quinzaine d’années mon équipe recherche une nouvelle stratégie pour éradiquer les cellules souches cancéreuses à l’origine des glioblastomes et leurs récidives en les privant de leur potentiel tumoral. Afin d’être au plus proche de la tumeur d’origine nous travaillons avec des cellules de patients. De fait, nos efforts se sont focalisés sur les glioblastomes de l’adulte opérés dans le service de neurochirurgie de Nice, en lien avec le Dr Almairac. Fin 2022, nous avons obtenu des cellules de DIPG en collaboration avec le Dr Junier pour un projet qui n’a pas été financé. Malgré cela nous avons débuté des travaux qui montrent que le candidat-médicament que nous avons développé sur le GB adulte pourrait être efficace contre le GB de l’enfant. Mes collaborateurs et moi sommes extrêmement mobilisés pour apporter une preuve de l’efficacité de ce traitement dans un modèle in vivo de DIPG. Sans évoquer la douleur des familles que l’on peine à réaliser lorsqu’on n’expérimente pas la perte d’un enfant dans sa chair, la mort d’un enfant malade du cancer est un fait social inacceptable qui pourrait être évité si plus de moyens financiers étaient dédiés à l’étude des cancers pédiatriques.



Dr Laurent TURCHI Suite au développement par votre équipe de recherche d’une petite molécule innovante pour le traitement du glioblastome, vous avez décidé de fonder Virtu Therapeutics. Pouvez-vous nous en dire plus sur cette initiative et les principales difficultés rencontrées ?

En effet, comme vient de l'évoquer Thierry, nous avons mis au point une stratégie thérapeutique innovante consistant à piéger les cellules souches cancéreuses à l’origine des Glioblastomes et de leurs récidives dans un état où elles sont devenues incapables de contribuer à la progression de la tumeur. Contrairement aux chimio et radio thérapies cytotoxiques, qui sélectionnent des cellules tumorales résistantes à l’origine des récidives, notre stratégie différenciante rend également les CSG sensibles aux traitements. Ces résultats obtenus sur des cellules de patients en culture et dans un modèle in vivo, nous ont incité à poursuivre le développement de notre candidat médicament dans un projet de création d'entreprise. Pour cela nous avons contacté deux professionnels de l’industrie de la santé et constitué une petite équipe pour démarrer le travail. Notre objectif prioritaire est de porter ce candidat médicament et notre stratégie thérapeutique en clinique chez l’adulte et l’enfant. Notre principale difficulté est que le Glioblastome est un cancer rare, les formes pédiatriques le sont encore plus et que les investisseurs que nous avons rencontrés nous ont incité à rechercher une efficacité dans des indications plus rentables… prédisant que sans cela nous aurions des difficultés à être financé.


Quel impact espérez-vous à terme pour les enfants concernés par des tumeurs cérébrales ?

Les résultats que nous avons obtenus dans des modèles de glioblastome permettent d’espérer stopper durablement la progression de la tumeur chez les enfants atteints d’un DIPG. Notre approche thérapeutique diminue la résistance des cellules tumorales au traitement et empêche la sélection de cellules plus agressives responsable des récidives. Ainsi, nous devrions assister à la diminution spontanée de la taille de la tumeur en traitement seul ou en combinaison avec une thérapie cytotoxique. Au stade de développement actuel, notre candidat médicament permettrait une augmentation de l’espérance de vie des enfants et des adultes atteints d’un glioblastome mais également l’amélioration de leur qualité de vie.

 
M Lionel Menou, après plusieurs années dans un grand groupe pharmaceutique et la mise sur le marché d’une biothérapie développée par une start up, vous avez rejoint le projet Virtu Therapeutic et présidez maintenant la société. Est-ce que le soutien de la fédération Grandir Sans Cancer, et de l’association Eva pour la vie, pour permettre le démarrage de cette start-up du médicament est important ? Pouvez-vous nous expliquer pourquoi ?

Quand Laurent Turchi m'a contacté début 2022, j’ai très vite réalisé la qualité du travail entrepris, et les perspectives d’applications thérapeutiques de ce candidat médicament pour le traitement des Glioblastomes pédiatriques et de l’adulte. Avec Patrice Cornillon, ancien dirigeant dans l’industrie du diagnostic médical, nous avons apporté le cadre nécessaire à la création de la start up. Notre travail et celui des chercheurs ont été récompensés par de nombreux partenaires locaux et nationaux dont l’incubateur PACA EST, l’Université de Nice et la Banque Publique d’Investissement (Aide BFTE). La qualité de notre projet nous a permis d'être lauréats du Concours National de l’Innovation (Aide iLab) en 2023. Paradoxalement, le versement des subventions institutionnelles (BFTE, ilab) est assujetti à la capacité de l’entreprise à cofinancer une partie du projet. C'est tout à fait normal, la création d'une start-up est une grosse prise de risque, mais notre stade de développement et notre indication médicale (Glioblastome de l’adulte et de l’enfant) ne nous ayant pas encore permis d’attirer des fonds d’investissement ou un partenaire industriel, le cofinancement devait provenir des co-fondateurs (ce qui a été fait au maximum, sachant aussi que nous ne nous rémunérons pas) et de la société civile.

Ainsi, nous avons sollicité la fédération Grandir sans Cancer et l’association Eva pour la Vie. Sans leurs soutiens financiers, Virtu Therapeutics, créée en décembre 2023, n’aurait pas été en mesure de percevoir les aides institutionnelles et donc démarrer le développement du candidat médicament. Leur contribution et au travers de celles-ci des familles concernées par les cancers pédiatriques auront été fondamentale pour notre société.


Grâce à l’implication de plusieurs députés et au soutien de la ministre de la recherche Frédérique Vidal, avec Grandir Sans Cancer et Eva pour la vie, 5M€/an sont alloués en faveur de la recherche fondamentale sur les cancers de l’enfant depuis fin 2018. Tout en saluant cette avancée, ces associations souhaitent que ce financement soit porté à 20M€/an et élargi à la recherche clinique oncopédiatrique. De même, elles militent pour que le gouvernement favorise à travers un financement fléché le développement de start-ups du médicament pédiatrique contre les cancers et maladies graves de l’enfant. Que pensez-vous de leurs propositions et qu’est-ce que cela pourrait apporter aux enfants atteints de cancers ?
 
Virtu Therapeutics: Faire progresser les connaissances sur les cancers pédiatriques et trouver des traitements adaptés aux situations bien souvent différentes de l’adulte devrait être bien plus qu’un axe scientifique prioritaire et sanctuarisé. Ce devrait être un projet politique avec la perspective de sauver chaque enfant malade d’un cancer. Cette recherche ne manquerait d’ailleurs pas de bénéficier aux adultes. A l’heure actuelle, c’est exactement la situation inverse. Bien que des efforts aient été faits ces deux dernières années pour financer la recherche sur les tumeurs pédiatriques, grâce à la vitalité de votre combat, on cherche pour le plus grand nombre parce que c’est là que sont faits les plus grands bénéfices en terme de santé publique mais aussi et surtout les retombées financières les plus sûres. Une recherche de qualité nécessite des moyens qualitatifs (niveau de formation des scientifiques, des médecins…) mais aussi quantitatifs. Pour cette raison nous souscrivons aux propositions portées par les associations auprès de nos parlementaires et du gouvernement.

Les progrès réalisés en matière de traitement et de soins de support ont permis d'améliorer le taux de survie à cinq ans des enfants atteints d'un cancer. Néanmoins, le traitement du cancer chez l’enfant est souvent toxique à moyen et long terme. Ainsi, les enfants ayant vaincu leur cancer ont un risque élevé d’avoir des maladies chroniques à l’âge adulte, dont principalement des maladies cardiaques et métaboliques.

Chez les enfants se battant contre un cancer, il a été démontré que l'activité physique adaptée (APA) a des effets positifs pendant et après le traitement : elle améliore la santé générale, l’activité du cœur, la force musculaire, la qualité de vie et réduit la fatigue. Cependant, les conséquences de la pratique d’une activité physique dès le diagnostic n’ont pas été abordées dans les études publiées à ce sujet, notamment en termes de tolérance métabolique des chimiothérapies et corticothérapies prolongées. De plus, aucune étude ne s’est intéressée aux effets sur les risques de maladies cardiaques ou métaboliques à long terme. Chez les enfants en bonne santé, on sait que l’APA améliore les paramètres métaboliques et réduit les risques de maladies métaboliques chroniques.

Ce projet consiste à déterminer si, comme chez les enfants en bonne santé, les bénéfices de l'activité physique sur la santé métabolique s'appliquent aux enfants traités pour un cancer, et ce, dès le diagnostic. Interview du Pr Marlène PASQUET et de Justine Thomas


Justine Thomas (JT) et Pr Marlène Pasquet (MP), pouvez-vous vous présenter ? 

JT : Je suis enseignante en Activité Physique Adaptée et étudiante en doctorat de sciences. Mon quotidien au sein du CHU est réparti entre les séances d’activités physiques adaptées aux patients soignés dans le service d’hématologie-oncologie ainsi que les activités liées au protocole de recherche APACIS (suivi, évaluation, analyse des données, congrès, communication).

MP : Professeure en Hématologie Oncologie Pédiatrique depuis plus de 15 ans maintenant dans le service HIOP à Toulouse. Dans le service je m'occupe plus spécifiquemment des enfants présentant des hémopathies, des patients avec maladie hématologique benigne et des enfant porteurs de déficit immunitaire. En tant qu'enseignante, je forme les étudiants en 5ieme année et les internes, et je dirige le groupe dédié aux maladies GATA2 au sein de l'équipe 16 du CRCT (IUCT-O, INSERM U1037). J'encadre Me Thomas Justine depuis son Master 2 et maintenant sa these de science dans ce projet.

Vous êtes à l’origine du projet « Activité physique adaptée chez l’enfant traité pour cancer et insulinosensibilité ». Pouvez-vous nous expliquer les principales raisons qui vous ont incité à rédiger ce projet ? A qui s’adresse-t-il et quel sera son déroulement ?

JT : Le protocole APACIS viens d’un constat récent, on soigne de mieux en mieux les cancers pédiatriques mais on manque d’éléments pour accompagner le post-cancer à long terme, notamment les séquelles métaboliques des traitements, qui peuvent donner lieu à des maladies une fois l’âge adulte atteint. On sait que l’activité physique est un moyen de prévention de ces maladies chez les adultes et les enfants sains, mais aucun travaux ne s’intéresse à cet effet chez des enfants soignés pour un cancer. C’est cette combinaison entre l’effet du sport et le risque métabolique qui a motivé notre travail. 

L’étude APACIS s’adresse à tous les enfants âgés entre 5 et 18 ans, soignés pour tout cancer au sein du CHU de Toulouse. Il consiste à pratiquer des activités physiques de manière encadrée pendant 6 mois, à l’hôpital ou au domicile, puis à être suivi pendant 2 ans. Des évaluations métaboliques sont effectuées à partir d’échantillons sanguins, ainsi que des évaluations de la santé physique et de la nutrition, pour garantir une approche globale. 

Quelles sont les perspectives et vos espoirs à l’issu de ce projet ?

JT : Nous travaillons sur la possible extension de cette étude à d’autres centres hospitaliers. Les résultats préliminaires sont encourageants avec des effets sur la toxicité métabolique et la tolérance des effets secondaires des traitements. Nous espérons que cette étude apportera les premiers éléments sur l’effet de l’exercice physique sur des facteurs métaboliques dans les cancers pédiatriques et qu’elle encouragera d’autres chercheurs à s’intéresser aux intérêts de l’activité physique adaptée chez ce public.

MP : les premiers résultats vont dans le sens de notre observation clinique: au dela du bien etre et de l'apport psychique évident de l'APA, la tolérance aux traitement semble meilleure depuis l'introduction précoce de l'activité physique adaptée. Le démontrer scientifiquement est un vrai challenge que nous relevons, à travers des analyses métabolomiques poussées et des analyses du microbiote salivaire, parodontal et fécal.

 
Au-delà de l’appel à la générosité publique, Eva pour la vie a impulsé dès 2012 une démarche inédite en Europe – désormais partagée par de nombreuses associations à travers la Dédération Grandir Sans Cancer – demandant à l’Etat à créer un fonds dédié à la recherche sur les cancers de l’enfant, ainsi qu’à améliorer l’aide aux familles d’enfants malades. Avec Grandir Sans Cancer, elle a obtenu fin 2018 le vote d’un fonds annuel dédié de 5M€/an pour cette recherche, et fin 2021, d’un rajout ponctuel de 20M€ supplémentaires en vue de favoriser la structuration des équipes. Elle mobilise actuellement les parlementaires afin que ce fonds soit porté à 25M€/an afin d’y inclure la recherche clinique oncopédiatrique. Elle souhaite enfin que les postes d’APA nécessaires soit systématiquement financée par le ministère de la santé pour l’ensemble des services d’oncologie pédiatriques. Que pensez-vous de cette mobilisation ?

JT : Je salue et remercie cet engagement sans faille d’Eva pour la vie de manière générale pour la recherche en cancérologie pédiatrique et pour l’APA. Notre métier est essentiel dans de tel service mais encore fragile ou précaire, l’engagement d’Eva pour la vie ainsi que de la fédération Grandir Sans Cancer nous a permis de recruter une deuxième enseignante en APA ; au delà de ça je pense que l’engagement associatif constitue un véritable atout pour convaincre le ministère de l’importance de notre fonction. 

MP : Cette mobilisation est courageuse, essentielle et capitale. Le financement de ces postes n'est absolument pas perenne dans aucun des CHU de France et de nombreux travaux scientifiques ont montré le bénéfice de l'APA sur la qualité de vie et l'amélioration des conditions post traitement. Notre étude vise à apporter des éléments scientifiques supplémentaires à ce bénéfice en terme de tolérance, et ce grace à une introduction précoce. Des travaux commencent à démontrer le bénéfice de l'APA sur le systeme musculaire, l'immunité et la cognition des enfants atteints de CAncer. Financer ces postes à un échellon institutionnel est une priorité et nous sommes tres enthousiastes de ce soutien apporté par Eva pour la vie et la fédération Grandir sans Cancer.

Eva pour la vie a apporté fin 2024 la somme de 10 000 € pour permettre - avec d'autres associations - le recrutement d'un poste d'APA (activité physique adaptée) au sein du service d'oncologie pédiatrique du CHU de Toulouse. Elle a également apporté une subvention de 20 000 € en faveur du projet de recherche « activité physique adaptée chez l’enfant traité pour cancer et insilunosensibilité (APACIS) – études ancillaires »

 

Dr Celio Pouponnot, pouvez-vous vous présenter en quelques lignes ? (votre rôle et activité au sein de l'Institut Curie)

Je suis directeur de recherche au CNRS et dirige une équipe de recherche composée de 12 à 14 personnes, sur le site d'Orsay de l'Institut Curie qui est réparti sur trois sites : Paris, Orsay, Saint-Cloud. Nos activités de recherche portent sur les tumeurs cérébrales de l'enfant et leurs traitements, en particulier la radiothérapie. Une partie importante de nos travaux concerne le médulloblastome, une tumeur pédiatrique du cervelet sur lequel porte le projet financé. Le médulloblastome est principalement pédiatrique, diagnostiqué à un âge médian autour de 7 ans. La survie à 5 ans est de 70-80%. Cependant, cette statistique masque la grande hétérogénéité de ces cancers, qui présente des groupes à risque variable comprenant des tumeurs de bas ou haut risque, le taux de survie de ces dernières étant beaucoup plus faible.

 

Vous êtes à l’origine du projet « Modélisation du médulloblastome grâce à l’utilisation d’organoïdes humains cérébelleux et analyse de l’effet des polluants agricoles ». Pouvez-vous nous expliquer les principales raisons qui vous ont incité à rédiger ce projet ? Quels sont ses objectifs ?

Le projet soutenu par Grandir sans Cancer et Eva pour la vie est dirigé par B Duvillié, chercheur INSERM dans l'équipe. Il est structuré autour de deux axes, le développement d'un modèle pour étudier le médulloblastome de haut risque et un deuxième où nous utilisons ce modèle pour étudier l'effet de polluants sur les phases précoces du processus tumoral, c’est-à-dire son initiation.

Les modèles d'étude sont des éléments clés de la recherche en cancérologie car ils permettent d'étudier différents processus. Dans ce projet, B. Duvillié développe un modèle de mini-organe in vitro, en boites de culture. En utilisant des cellules humaines immatures, appelées cellules souches pluripotentes induites, nous pouvons obtenir une structure en 3 dimensions qui ressemble à un mini-cervelet humain. En y introduisant des gènes altérés dans le médulloblastome, nous sommes capables de modéliser le médulloblastome de haut risque. Même s'il a ses propres limites comme tout modèle d'étude, il permet notamment d'étudier les étapes initiales de la tumorigenèse et les effets des polluants sur ces étapes initiales.

Dans la première partie du projet, nous cherchons à améliorer ce modèle en y ajoutant des cellules qui forment les vaisseaux sanguins pour le rapprocher de l’organe réel. A l'avenir, nous y ajouterons des cellules immunitaires pour mieux comprendre leur rôle dans l'initiation tumorale, la réponse aux thérapies anti-cancéreuses ou leur impact en cas d'exposition aux polluants.

Dans la deuxième partie du projet, nous analyserons l’impact de certains polluants (insecticides ménagers, antifongiques agricoles) sur les étapes précoces d'initiation du médulloblastome. Le rôle des polluants dans l'apparition des cancers de l'enfant constitue une question sociétale importante, comme nous avons pu le voir récemment mais seules des réponses scientifiques partielles ont été apportées. En tant que chercheurs, notre rôle est de faire avancer la science sur des questions de recherche fondamentale et clinique mais également, quand nous le pouvons, sur ces débats sociétaux. Nos travaux sur les polluants s'inscrivent dans un cadre plus large. En effet, diverses équipes de recherche travaillent sur ces problématiques, notamment le consortium PEDIAC dans lequel nous sommes impliqués et dont les thématiques portent sur les causes et les origines des cancers pédiatriques. Ce consortium permet d'allier études épidémiologiques et recherche expérimentale. Nous espérons ainsi pouvoir contribuer à amener des réponses mêmes partielles à ces questions importantes de l'implication potentielle des polluants dans les cancers de l'enfant.

Quelles sont les perspectives et vos espoirs à l’issu de votre projet de recherche ?

Nous espérons améliorer les modèles d'étude du médulloblastome en nous rapprochant le plus fidèlement possible de la pathologie et les partager avec la communauté scientifique. Ces modèles devraient nous permettre de mieux comprendre cette pathologie pédiatrique, notamment ses causes et de contribuer, ainsi, à mieux la traiter. Concernant les polluants, nous espérons que nos recherches participeront à la clarification de leurs impacts potentiels dans les cancers pédiatriques. Notre étude expérimentale ne fournira pas de réponses définitives mais pourrait apporter des faisceaux d'indications sur la potentialité des polluants à modifier la cellule d'origine de ces cancers et participer, ainsi, à l'amorçage ou l'accélération du processus cancéreux. Il sera essentiel de compléter notre étude avec des modèles in vivo plus complexes qui permettent d'apporter des réponses complémentaires. Notre étude s'inscrit dans un champ pluridisciplinaire incluant l'épidémiologie, la toxicologie (…) qui, toutes ensembles, devraient contribuer à apporter des réponses à ces questions sociétales d'importance.

Généralement, les parents d'enfants atteints de cancers s'interrogent sur les causes de cette maladie, dont l'incidence ne diminue pas en France comme en Europe. Si dans 10% des cas, des facteurs génétiques sont mis en évidence, dans la nette majorité des cas, les médecins n’en connaissent pas les causes. Beaucoup de parents s'interrogent sur les facteurs environnementaux et les polluants, tout en ayant un certain sentiment d'impuissance, car quoi prévenir, contrairement à l'adulte, chez des enfants qui ne boivent pas d'alcool, ne fument pas, qui s’alimentent correctement et qui font de l’exercice physique ? Que souhaitez-vous dire à ces parents ?

Il est important de préciser que les 10% de facteurs génétiques en question concernent des prédispositions héréditaires ou mutations congénitales. Néanmoins, de fréquentes altérations génétiques sont identifiées dans les cancers pédiatriques tels que des mutations, altérations chromosomiques… Ces altérations génétiques dites "somatiques" sont clairement impliquées dans le processus cancéreux, sont très fréquentes et trouvées dans la quasi-totalité des cancers de l'adulte comme pédiatriques. L’enjeu scientifique réside dans la compréhension de l’origine de ces altérations : sont-elles provoquées par des facteurs environnementaux ou apparaissent-elles au hasard ? Des études scientifiques ont montré que ces altérations génétiques sont beaucoup plus fréquentes dans les organes en forte prolifération/croissance. Une des caractéristiques des organes des enfants est justement cette croissance/prolifération importante. Il est donc vraisemblable qu'une partie de ces altérations somatiques soient expliquées par ce phénomène. En parallèle, des études ont établi, par exemple, qu'une exposition aux rayonnements ionisants ou une habitation à proximité de grandes cultures viticoles augmente le risque de cancers pédiatriques. L’environnement et les expositions ne doivent donc pas être négligés, et davantage de recherche est nécessaire pour préciser leurs rôle et contribution. C'est précisément le but de notre projet.

Au-delà de l’appel à la générosité publique, Eva pour la vie a impulsé dès 2012 une démarche inédite en Europe – désormais partagée par de nombreuses associations et professionnels à travers la fédération Grandir Sans Cancer – visant à obtenir de l’Etat un fonds dédié à la recherche sur les cancers de l’enfant, ainsi qu’une amélioration de l’aide aux familles d’enfants malades ou décédés. Avec Grandir Sans Cancer, elle a obtenu fin 2018 du ministère de la recherche un fonds annuel de 5M€/an dédié à la recherche fondamentale sur les cancers de l’enfant, et fin 2021, un apport ponctuel de 20M€ en vue de favoriser la structuration des équipes de recherche sur les cancers pédiatriques. Elle est également étroitement liée à plusieurs progrès sociaux pour les familles concernées. Elle mobilise actuellement les parlementaires afin que le fonds de recherche soit porté à 20-25M€/an afin d’y inclure la recherche clinique oncopédiatrique. Elle souhaite que la mobilisation des pouvoirs publics soit durable, stable et axée, en même temps, sur la recherche, le soin, la prévention et un accompagnement social à la hauteur des besoins. Que pensez-vous de cette démarche ?

Ces dernières années, le soutien public pour la recherche en cancérologie pédiatrique a pu être renforcé grâce à la mobilisation des associations.  Les fonds obtenus ont permis de mobiliser de nouvelles équipes de recherche sur ces thématiques. La recherche devient de plus en plus coûteuse. Ces fonds sont donc cruciaux pour développer une recherche en cancérologie pédiatrique ambitieuse et de qualité afin de comprendre les causes, la biologie des cancers pédiatriques, mais également l'impact de l'exposition aux polluants, les mécanismes de résistance aux traitements et leurs toxicités… La diversité et la combinaison des approches (clinique, épidémiologique, toxicologique, fondamentale) est nécessaire pour progresser dans la compréhension de ces pathologies. Il est donc essentiel que ces initiatives se poursuivent et soient entendues car les fonds qu'elles ont permis de débloquer représentent une aide indispensable pour l'avancée de la recherche en cancérologie pédiatrique.