Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood in Europe. The prognosis of ALL has significantly improved during the past decades, mainly due to standardized chemo- and radiotherapy regimens. There has been a big push to identify novel therapies for genetically high-risk cases, yet most relapses in ALL (20-35%) occur in low-to-intermediate risk patients experiencing slow therapy responses. In our previous GEPARD project, we identified several genes and pathways in “low-to-intermediate risk” B-ALL that could be targeted with specific therapies. This underscores the need for a better understanding of the biology of these genetic subtypes to avoid overtreatment of undertreatment.

Building on the previous GEPARD project, we will continue to investigate and validate the impact of the identified genetic changes. Our goals include identifying circulating biomarkers to distinguish the “true” high-risk patient population from the “low-to-intermediate-risk” group. Additionally, we will conduct further drug screens for targeted therapies in ETV6::RUNX1 and TCF3::PBX1 subtypes, and study the effects of dasatinib targeted therapy in both T-ALL and B-ALL, combined with promising new drugs in preclinical and early phase clinical trials.

This study will be a transnational, multidisciplinary effort, integrating modern multi-omics analyses of patient samples and preclinical models with the development of novel AI-based tools and innovative high-throughput drug screens. These pioneering efforts aim to advance personalized treatment strategies in early phase clinical trials. The analysis workflows developed in this study will have broader applicability across a wide range of genetically-based diseases, extending beyond the pediatric leukemias being investigated.