Evaluation of the in vivo efficacy of PRIMA-1MET and its synergistic interactions with the combined inhibition of RAS-MAPK and AKT-mTOR in neuroblastoma
Neuroblastoma (NB) is the most common extra-cranial solid tumor in children, accounting for 7-8% of all childhood malignancies and 15% of all cancer-related deaths in this population. It is the most common cancer diagnosed in early childhood, with the median age at diagnosis being around 19 months. While 90% of patients are under 5 years of age, NB is very rare after the age of 10. Metastatic disease is present in approximately 50% of cases.
Children in the very low-risk subgroup have an expected long-term survival rate of 99% to 100%, while patients in the high-risk subgroup have a long-term survival rate of less than 50% despite intensive multimodal therapy including surgery, high-dose chemotherapy with autologous bone marrow transplantation, radiation therapy, and immunotherapy. New therapies for the high-risk subgroup are therefore urgently needed.
In recent years, the Neuroblastoma group of the CANSEARCH research platform has focused on the search for new treatment options for patients with neuroblastoma, a tumor that is particularly aggressive in metastatic forms. We have published very interesting results, in particular on a small molecule, PRIMA-1MET (APR-246 or eprenetatpopt), which is known to reactivate the p53 protein and its interactions with the various signaling pathways important in neuroblastomagenesis.
With the advent of CRISPR/Cas9 technology, we have access to a new tool to investigate new leads, particularly in the field of synthetic lethality.
The aim of our current project is to develop the technology for screening CRISPR/Cas9 libraries in neuroblastoma in order to identify additional synergistic genetic targets in the context of already established therapies in neuroblastoma, in particular with eprenetatpopt, ALK inhibitors and cisplatin.
In addition to these activities, we will also continue to analyze relevant data available to the public, from the INRG consortium, to study the clinical importance of certain genetic markers and their combination.
What does this study bring to patients?
The Neuroblastoma project makes it possible to improve knowledge about the functioning of cellular signaling pathways within neuroblastoma tumor cells and to identify important factors in order to have a better understanding of the aggressive behavior of this disease and to develop better therapeutic strategies.
