High-Grade Gliomas in Children
High-grade gliomas are the most common malignant tumors in children and adolescents. Our understanding of these cancers, particularly gained during the BIOMEDE trial led by Dr. Jacques Grill, has led to better defining and understanding these diseases. Now that we know that malignant gliomas in children and adults are not alike, tailored therapeutic strategies must be developed. Thanks to the BIOMEDE, MICCHADO, and MAPPYACTS projects, very specific mutations, never described in any other cancer, in genes regulating DNA organization and its expression have been described in these tumors. This discovery thus reorients therapeutic strategies to target these genes involved in DNA structure or expression.
About the Project
High-grade pediatric gliomas frequently express mutated forms of a protein called histone H3.3, which has established functions in DNA damage repair. Dr. Rondinelli’s team has identified a DNA repair defect in cells mutant for H3.3, which confers dependence on a specific DNA repair enzyme, polynucleotide kinase-phosphatase (PNKP). PNKP underlies aberrant DNA repair in tumor cells and proliferation of H3.3 mutant cells.
In this project, researchers aim to characterize this target in detail and develop the therapeutic potential of targeting it in pediatric gliomas. Initially, they will analyze its specificity towards mutant H3.3 cancer cells and characterize the genetic determinants and mechanism underlying the anti-proliferative effect of PNKP targeting in tumor cells. Current chemotherapy and radiotherapy treatments do not completely and durably kill glioma tumor cells. Therefore, they propose to evaluate their combination with PNKP targeting to reduce cancer cell proliferation in pediatric gliomas. Secondly, they will leverage preclinical models to predict the treatment’s efficacy in patients with pediatric gliomas. The efficacy of PNKP targeting will be assessed particularly in murine models of brain tumors.
By providing comprehensive proof of principle of PNKP targeting in pediatric gliomas, this work should lead to a new therapeutic strategy targeting aberrant DNA repair in these tumors, which have so far been almost incurable. Thus, this work should stimulate the development of specific PNKP inhibitors and pave the way for new phase I clinical trials aimed at better treating this disease with a bleak prognosis.
Project Summary
- Promoter: Gustave Roussy
- Principal Investigator: Dr. Béatrice Rondinelli
- Program Duration: June 2023 – June 2025
- Countries involved: France
- Funding from Imagine for Margo: €40,000
This trial was co-funded by the Rallye du Cœur de Paris 2023 and was selected as part of the SFCE’s 2022 call for projects.
