Project Summary / Abstract Despite progress in understanding the molecular basis of childhood malignancies, cancer remains the leading cause of disease-related death in school age children. Moreover, we are still treating these children with old approaches, including cytotoxic chemotherapy, radiation, and surgery, each with associated morbidities. Several roadblocks have hampered progress in treating children with cancer. First, cancer-promoting targets, such as transcription factor fusion oncoproteins, are quite common in pediatrics but make for challenging drug targets. Second, pediatric malignancies tend to have fewer mutations than adult cancers resulting in a decreased likelihood of response to immune checkpoint inhibitors. In sharp contrast, immune checkpoint inhibitors have transformed therapy for subsets of adult cancers. Third, there is a market disincentive for pharmaceutical companies to work on targets that are exclusive to pediatric cancers. Academic investigators must take the lead in de-risking these high priority pediatric targets through comprehensive target validation and identification of initial chemical leads. I am an investigator willing and equipped to take such a risk. I am a physician-scientist, pediatric oncologist innovator and have dedicated my career to the goal of precision pediatric oncology medicine. The time is right to tackle these vexing challenges in childhood cancer therapy development. I will focus predominantly on fusion-driven acute myeloid leukemias (AMLs) and the fusion- driven pediatric solid tumor Ewing sarcoma, two areas of deep expertise in my laboratory. The first objective of my future research program is to target oncogenic fusions in pediatric cancers. We will pioneer new strategies of targeted protein degradation to validate and mechanistically dissect their role in tumor maintenance and to develop inhibitors/degraders that will ultimately inform new therapies. I have led innovative chemical and functional genomic approaches to identify therapeutic targets for childhood cancer, such as the first Pediatric Cancer Dependency Map, genome-scale CRISPR-Cas9 screening in over 100 pediatric cancer models. Novel pediatric specific targets and innovative therapeutic concepts have emerged and will be the focus of our second objective. We aim to deeply understand these targets mechanistically and to identify chemical perturbagens of the top priority dependencies by deploying innovative chemical biology strategies. My third objective leverages my expertise in functional genomics and epigenetics to identify and drug the regulators of key targets of immunotherapies in childhood cancer. My success in these bold endeavors will be ensured by a collaborative team of world-class chemists, structural biologists, immunologists, and epigenetics experts. The discovery of drugs that target pediatric oncogenic fusions and other novel Achilles heels, and the converting of unresponsive childhood malignancies to immunothera...