Brain tumours are among the most common and deadly solid tumours in children, adolescents, and young adults. Despite improvements in treatments such as chemotherapy, surgery and radiation therapy, the outlook for patients with a high-risk tumour is poor. In recent years, there has been little progress in the development of new drugs for brain tumours.Cancers are caused by abnormal genetic mutations that accumulate over time. These mutations lead to treatment resistance.
Poly (ADP-ribose) polymerase inhibitors (PARPi) are drugs developed to treat cancers caused by specific genetic mutations. PARPi work by preventing cells from repairing themselves, leading to those cancer cells death.Combining PARPi with chemotherapy has been shown to improve outcomes in other cancers and is now being studied for use in paediatric cancers too, such as brain tumours.The aim of this project is to study NIRAPARIB, a type of PARPi that can cross the ‘blood brain barrier’, in combination with IRINOTECAN, a chemotherapy used in several brain tumours. The first part of the study will focus on defining a well-tolerated dose and administration schedule. The second part of the study will evaluate the efficacy of this new treatment.This study will be part of the platform study Access Secured – European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumours (AcSé-ESMART). The study plans to enrol 58 patients over 2 to 3 years in 7 European countries.If this study shows encouraging results, NIRAPARIB with IRINOTECAN will be used in larger disease-specific studies to improve survival in patients with those specific brain tumours.

Classical Hodgkin lymphoma (cHL) accounts for 15% of all cases of cancer in children and adolescents and represents the first cause of cancer during adolescence with nearly 120 cases of pediatric cHL in France and 160 cases in Germany each year.

While excellent long-term survival has been achieved in children and adolescents with Hodgkin lymphoma using radiation, multiagent chemotherapy, and combined-modality therapy up to 10-15% of patients still experience recurrent or primary refractory disease. Thus, as more than 90% of pediatric patients are cured after the first line treatment, a major emphasis is placed on survivorship by reducing treatment intensity, in particular, the use of radiotherapy and chemotherapy both associated with long-term toxicities.

The risk stratification, which means to give the most appropriate treatment to the patient according to his proper risk of relapse, is the cornerstone of the treatment in cHL. The reliability and utility of some imaging exam in pediatric HL in this indication was well reported but suffered from several limitations failing to identify some patients with future relapse or wrongly considering as refractory. We aim to develop a biological marker tool, which could sharpen the initial risk stratification, improve the assessment of disease evaluation during the treatment and beyond and facilitate the detection of relapse.

This marker could be the circulating tumor DNA (ctDNA). ctDNA is found in the bloodstream and refers to DNA that comes from cancerous cells and tumors. Tumor cells in cHL are multinucleated giant cells named Hodgkin and Reed-Sternberg (HRS). Several studies (mostly in adult cHL) have already reported that ctDNA evaluation issued from the HRS cells could be a relevant biological marker to predict the response to chemotherapy and the subsequent risk of relapse.

In the EurHOLY project we aim to leverage the expertise and the recruitment issued from two major countries (France and Germany) involved in the largest therapeutic trial for pediatric cHL (Euronet-PHL C1 and C2). Both countries have already collected more than 500 ctDNA samples issued from pediatric patients with cHL. We plan to perform a combined analysis issued from our two on-going studies exploring ctDNA in pediatric cHL and this integrated analysis will lead us to conduct a prospective trial evaluating the role of ctDNA in 400 pediatric patients suffering from cHL. The final objective of the EurHOLY project is to pave the way for the future integration of ctDNA evaluation in the next international pediatric cHL trial.

Brain tumours are among the most common and deadly solid tumours in children, adolescents, and young adults. Despite improvements in treatments such as chemotherapy, surgery and radiation therapy, the outlook for patients with a high-risk tumour is poor. In recent years, there has been little progress in the development of new drugs for brain tumours, including medulloblastoma.This lack of new drugs is caused by the difficulty to screen new drugs preclinically as potential candidates for the clinic. The most commonly used technique for preclinical testing, two-dimensional culture models in petri dishes, poorly represents the complex behaviour of the drugs in patients; as a result, the results of such culture are not very reliable and there is a big discrepancy between the preclinical results and what is observed in the clinic.

Preclinical testing on mouse models is much more reliable (what is observed in a mouse is more likely to work in the clinic) but not very efficient in terms of number of drugs that can be tested.

Recently, the development of what is called “organoids” or miniature replication of human organs, has paved the way to a more reliable and faster technique to test new drugs preclinically as it can test up to thousands of drugs in one batch.

The “Medullodrug” team developed the first human organoid-based model for paediatric medulloblastoma and paediatric high-grade glioma opening the door for gaining unprecedented new knowledge into the development of paediatric brain cancer directly in a human system.

The aim of this project is to identify promising drugs, among drugs that have already been authorised, to initiate new clinical trials in Medulloblastoma.

Brain tumours are among the most common and deadly solid tumours in children, adolescents, and young adults. Despite improvements in treatments such as chemotherapy, surgery and radiation therapy, the outlook for patients with a high-risk tumour is poor. This is especially true for Diffuse Intrinsic Pontine Gliomas (or ‘DIPGs’) which are almost completely incurable.One obstacle to the development of efficient therapies for DIPGs was the lack of appropriate in-vitro models recapitulating with accuracy the characteristics of DIPGs. Moreover, most treatments used for this disease were developed for adults and show limited effect on children.

Recently, the development of what is called “organoids” or miniature replication of human organs, has paved the way to a reliable and faster technique to test new drugs preclinically as it can test up to thousands of drugs in one batch.

It has already been demonstrated that DIPG has a specific epigenetic profile; this project will also attempt to identify epigenetic dependencies and vulnerabilities of DIPGs.

Epigenetics is the science which explains gene coding: it allows us to understand why cells with the same genetic code have different functions inside someone’s body. Think about a very long book from which some words would be highlighted in different colours to create several alternative plots.

As a result, this project will set the basis for the development of novel and personalised therapeutic strategies for this paediatric disease.

Acute lymphoblastic leukaemia (ALL) is the most common cancer in children, which can affect either B- or T-cells (B or T-ALL). The current cure rate amounts to about 80 % of all patients.When a child with T-ALL does not respond to the initial treatment (“resistant disease”) or sees its cancer come back (“relapse”), his or her chance to cure falls below 25%. To improve those patients’ chances of survival, we need to improve our understanding of the T-ALL biology and to identify “biomarkers” that will help us to understand which patients are most likely to resist to treatment or relapse.

However, research into an improved understanding of T-ALL mechanisms is difficult because the number of patients per country is limited. To overcome this, 14 European countries have joined forces to develop one single clinical trial for children and AYAs called “ALLTogether1”. This wide clinical trial brings together a critical number of patients’ samples (200 new patients with T-ALL per year) that can be studied to improve our understanding of T-ALL resistance mechanisms.

This study aims at analysing changes in genes and proteins in resisting T-ALL cells, after expansion of these cells in mice. The researchers will use artificial intelligence to create computer simulations of the composition of the leukaemia cells to predict response to novel treatments. In addition, leukaemia cells will be tested in the lab to understand how possible combinations of existing drugs can kill leukaemia cells.

This project, in connection with the ALLTOGETHER clinical trial (14 countries), aims at developing a test platform to determine the combinations of existing drugs that will effectively treat leukemia cells.

Brain tumours are among the most common and deadly solid tumours in children, adolescents, and young adults. Despite improvements in treatments such as chemotherapy, surgery and radiation therapy, the outlook for patients with a high-risk tumour is poor. In recent years, there has been little progress in the development of new drugs for brain tumours, including gliomas.The ability to detect molecular changes in tumours has led to improved therapies, which act by disrupting cancer-specific mutations. These targeted therapies are now increasingly used in clinic, often as personalised treatment attempts for children with high-risk cancers, who have exhausted all other standard therapeutic options. Meaningful responses to targeted therapies are seen in some but not all patients. Even when patients respond to treatment, long-term tumour control is rarely achieved, and treatment fails after a time as cancer cells start developing resistance to the novel targeted drugs.

This study aims to understand this development of drug resistance during treatment and optimise the current standard tumour profiling approaches to increase detection of drug-resistant cells.

Researchers will sequence the tumour at a single-cell level. This will help to understand how, within a tumour, different cell populations reprogram their survival strategies to escape targeted therapies. Both the disease and mimic treatment will be modelled in a lab: researchers will compare glioma tumour samples from patients that responded to targeted therapies to those that did not. Such an in-depth approach will hopefully enable to capture changes in individual cells to understand how those cells overcome the most cutting-edge therapies.

This study aims to increase the efficacy of these therapies and prevent treatment failure. This knowledge can be used to refine therapy, enabling clinical trials to improve the selection and implementation of targeted therapies, with the ultimate objective to improve survival for children and adolescents with high-risk cancers.

One third of children with cancer will undergo radiotherapy as part of their standard treatments.
Children with cancer, unlike adults, are still in development, which makes them very sensitive to radiations. As a result, radiation therapy can cause many long-term side effects: short stature, irregular body proportions, leg-length differences, or spinal curvature.These disorders are called skeletal late-effects, and when they are very severe, they can be painful and debilitating, whilst milder forms can still disrupt routine activities for survivors.Irradiations on a growing bone can reduce its growth or cause one side of the bone to grow more than the other, making it curve. Growing bones are not normally the intended target of radiotherapy. Unfortunately, as radiation oncologists often cannot entirely avoid this growing bone, they will intentionally irradiate it as evenly as possible to reduce the risk of curving.More than European 2,750 children will receive spinal irradiation every year. The consequences are severe, with reduced final height and irregular body proportions. Despite radiation oncologists´ best efforts, approximately 900 of these children will still develop spinal curvature.When the skeleton stops growing at the end of puberty, these changes become permanent, and these childhood cancer survivors have limited treatment options. Given that the long-term survival of these patients is increasing, tens of thousands of individuals will be affected over the course this century.For this project, researchers will develop state-of-the-art models to understand the underlying causes of radiation damage to the growing skeleton and test strategies to prevent the development of skeletal late effects.

Brain tumours are among the most common and deadly solid tumours in children, adolescents, and young adults. Despite improvements in treatments such as chemotherapy, surgery and radiation therapy, the outlook for patients with a high-risk tumour is poor. This is especially true for Diffuse Intrinsic Pontine Gliomas (or ‘DIPGs’) which are almost completely incurable.

Considerable progress has been made in survival of young patients with many types of paediatric cancer, thanks to the positive impact of immunotherapy on new treatment strategies. Unfortunately, so far, chemo- and immune-therapies against DIPGs have been investigated without success, mainly because of the blood-brain barrier, which prevents an adequate drug delivery to the tumour located in the brain. Besides, macrophages and microglia (immune cells located in the tumour) shut off the immune system and prevent it from recognising and killing tumour cells, which enables the tumour to further its growth.

As immune cells can reach every part of the body, even distant ones, the use of immunotherapy for brain tumours offers an efficient solution to hunt down the most distant tumour cells. Immunotherapy could even thwart the impact of macrophages and microglia and make them work against the tumour cells by helping them to recognise the “foreign nature” of brain tumour cells.
This project will try to bring into the brain tumour therapeutic agents that reactivate these macrophages and microglia, using non-invasive ultrasound waves to open the blood-barrier.

By bringing in therapeutic agents that modify the infected immune cells, the immunosuppression in the tumour can be altered to our advantage. This means that the immune system can improve its ability recognise and kill the cancer cells, not only locally, but also cells that have moved to different parts of the brain. If successful, this will lead to an increase of the survival rate and a better quality of life for children with brain tumour.

Ewing’s sarcoma is a malignant solid tumour that most often affects young patients (80% of patients are under 20 years old).
The standard treatment for Ewing’s sarcoma includes chemotherapy and local treatment with radiotherapy or surgery when possible. Despite this heavy treatment, the chances of survival for these young patients, when their disease is metastatic at diagnosis, amount to 30% only and half of the relapses occur already while in treatment. Over the last decades, no new effective drugs have been introduced in the frontline treatment. It is high-time we try to improve the chances of survival for those patients.In the years 2010, a new treatment against a specific target called IGF-1R, which is predominantly present in Ewing’s sarcomas, showed promising results in some patients. However, we have not been able so far to identify which patients would really benefit from this drug.This project will study samples from patients included in a closed clinical trial where an IGF-1R inhibitor was tested to identify a biomarker that could tell apart patients that responded from those who did not respond.Besides, a new clinical trial will open shortly in the framework of ESmart where a new antibody called ‘Istiratumab’ will be tested that can target not only IGF-1R but also ERBB3 (a “bis-specific” antibody). This clinical trial will be open to young patients with Ewing’s sarcoma or other tumours with a potential implication of IGF-1R.The researchers will perform biological studies with fresh tissue of patients’ tumours, collected before inclusion in the ESmart clinical trial, and with plasma collected during the study. A large panel of new technologies will be used to screen all biological elements which could be involved in the response or resistance to treatment, with extensive next-generation sequencing for study DNA and RNA and very promising techniques to study proteins and metabolites (proteomics and metabolomics).These new technologies will be used to improve our understanding of the role of IGF-1R in the carcinogenesis of Ewing Sarcoma.
The results could lead to an improved selection of patients for the next clinical trials with targeted therapy against IGF-1R and allow the development of new therapeutic strategies for patients with resisting or relapsing Ewing sarcomas.