ABSTRACT Background Survival rates for children with solid tumors, including brain, have largely plateaued over the past three decades making them the most common cause of disease-related mortality in this age group. After decades of optimizing chemotherapy and radiotherapy protocols, higher cure rates for childhood solid tumors will no longer be achieved by “more of the same.” Rather, cures will require innovative interventions that specifically target the unique biology of these tumors, which are often driven by oncogenic fusions and other pediatric-specific oncoproteins historically considered difficult drug targets. With advances in targeted protein degradation and chemical interventions to inhibit protein-protein interactions, it has recently become tractable to target these proteins previously thought to be “undruggable”. Moreover, unbiased functional screening approaches, such as CRISPR- Cas9, have revealed new pediatric cancer synthetic lethal liabilities in need of targeted inhibitors. Aims We aim to lead the transformation of delivering such specific treatments to our young patients harnessing the power of a highly interdisciplinary and collaborative team of world-leading experts in pediatric oncology, targeted protein degradation, high-throughput chemical screening, medicinal chemistry, structural biology, tumor biology, preclinical drug testing, and clinical trials, complemented by a trans-Atlantic group of engaged patient representatives. Methods A bold plan will be pursued with a portfolio of projects that balance very high-risk efforts with others nearing clinical implementation. We will focus on drivers/targets in the following diseases: Ewing sarcoma, neuroblastoma, synovial sarcoma, ependymoma and high-grade glioma. We will explore different approaches to target these as yet undrugged paediatric drivers/dependencies, to overcome resistance to available targeted inhibitors, and to improve the efficacy and therapeutic window of CAR-T treatments. How the results will be used The aspiration of our team is to establish a sustainable platform for repeated developmental cycles of paediatric- specific drug development for emerging targets including a viable financial model to de-risk such developments for such rare pediatric tumors to the direct benefit of our patients. Specifically, we anticipate success through (i) delivering at least one optimised protein degrader for its application in early-phase clinical trials, (ii) enabling the druggability of previously “undruggable” targets, (iii) providing mechanistic insights into disease, novel targets, and therapy resistance mechanisms and ways to tackle them.