Children’s Neuroblastomas
Neuroblastoma is an extra-cerebral malignant tumor that develops from primitive nerve cells, called neuroblasts, which normally form the body’s nerve cells. This type of solid tumor is one of the most common in children. This cancer originates from the sympathetic nervous system (which prepares the body for intense activity) in the abdomen and sometimes in the adrenal glands, located just above the kidneys, or along the spine. This cancer can, more rarely, also develop in the nerve ganglia located in the neck, chest, or pelvis.
This disease represents 10% of solid tumors in children under 15 years old and mainly affects young children as it is usually diagnosed before the age of five (90% of cases). More than half of the children have a disease that is metastatic at the time of diagnosis. The exact causes of neuroblastoma are unknown, but genetic and environmental factors seem to play a role in its onset.
About the Project
High-risk neuroblastoma (HR-NB) is a childhood cancer with a very grim prognosis, despite recent scientific advances that have improved understanding of this disease. In order to develop new drugs targeting the genetic abnormalities carried by the tumor, studying alterations in genes responsible for HR-NB is essential. Experience gained from the use of targeted therapies for other diseases has shown that an initial phase of tumor response is generally followed by a phase of disease progression and treatment resistance. This may be due to the persistence of a small number of cells (or “clones”) resistant to treatment present at the beginning of the disease or to the emergence of new resistant “clones” during treatment.
It has long been known that there is tumor heterogeneity in HR-NB, meaning that it is composed of several different types of cells. More recently, next-generation sequencing (NGS) gene sequencing techniques have confirmed this observation. HR-NB is a heterogeneous disease, composed of different cellular clones, characterized by genetic abnormalities unique and distinct from neighboring clones. Analyzing this clonal heterogeneity within each tumor would help determine which clones are likely to determine tumor behavior, whether through their role in tumor initiation, metastatic spread, treatment resistance, or relapse.
The aim of this study is therefore to investigate the clonal evolution of HR-NB under targeted therapy, i.e., how different clones behave under the influence of drugs targeting their specific genetic abnormalities, compared to conventional chemotherapy. For this purpose, mouse models carrying a tumor (PDX, patient-derived xenograft) will be treated with targeted drugs and clonal evolution analysis will be measured using circulating tumor DNA (ctDNA) analysis. ctDNA consists of small fragments of DNA released by tumor cells into the blood. It is possible to isolate ctDNA from the blood and identify the different cellular clones using recent sequencing techniques. By leveraging the expertise of Dr. Schleiermacher and her team in ctDNA analysis, they aim to study tumor heterogeneity and clonal evolution of HR-NB under targeted treatment, with the ultimate goal of understanding potential mechanisms of resistance and therapeutic escape occurring during and after treatment.
Project Follow-up:
- Started in 2019
- 55 Drugs screened & 6 NB models used
- Alterations found: MycN, ALK, P53, ATRX, NF1, CD4, HRAS, and ARID1A
- The strongest tumor regressions were observed with lorlatinib alone or in combination with doxorubicin.
- The research team attempted to identify CNVs (different versions of a gene) between different tumors and following different treatments. 75% of them remained stable.
- In some cases, treatments led to genetic modifications allowing tumor cells to resist treatments or increase their proliferative capacity.
- This translational research did not identify common modifications that could be effectively targeted.
- Presentation of the project at the ANR congress 2023 and publication in a major journal is ongoing.
Project Summary
- Promoter: Institut Curie
- Principal Investigator: Dr. Gudrun Schleiermacher
- Program Duration: May 2019 – February 2024
- Countries involved: France
- Funding: Imagine for Margo – €120,000
