Medulloblastoma is the most common malignant brain cancer in children. The current therapeutic approach combines surgery, craniospinal radiotherapy and chemotherapy. Over the past three decades, this approach has been refined through empirical clinical research protocols and this once fatal disease now has a cure rate of approximately 70%. Notably, novel drugs have not significantly influenced treatment during this time and the survival rates for medulloblastoma patients have plateaued, indicating that conventional therapy has achieved its full potential and we have reached an inflection point. Given, the only opportunity to cure medulloblastoma is during front-line therapy following initial diagnosis, our strategy to improve the 30% failure rate for children with medulloblastomais through new agents that enhance the efficacy of current treatments and have potential to be included in a front-line clinical trial.This has led to the development of an evaluation pipelineinvolving three independent laboratories in Australia and USA,that includes screening drug libraries for agents active against patient-derived medulloblastoma cells, prioritising compounds that can cross the blood brain barrier and identifying those that enhance the activity of the treatments used in the clinic, e.g. traditional chemotherapy. An in vivocerebral microdialysis approach is used to verify CNS penetration. To confirm in vivoefficacy and identify the “best-in-class” agent, drug combinations are tested in a multitude of different mouse models, including genetically engineered mouse models and patient derived xenografts, representing different molecular subgroups of medulloblastoma. To maximise the chance of success for the identified novel combinations in a clinical trial, results are validated in independent laboratories, using additional mouse models. This presentation will reveal how this approach has resulted in the development ofSJ-ELiOT, a clinicaltrialcombining the cellcyclecheckpoint kinase 1 and 2 (CHK1/2) inhibitor, prexasertib, with conventional chemotherapies for children, adolescents and young adults with relapsed medulloblastoma.