Project 1: Optimization of therapeutic approaches for children with relapsed sarcomas using precision medicine.

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In children diagnosed with solid tumors, approximately 30% will die due to relapsed and refractory disease. Therefore the discovery and implementation of innovative approaches to therapy that minimize undesirable treatment-associated side effects are a critical unmet clinical need. Our multidisciplinary team comprised of clinical, bioinformatics, and basic researchers are pursuing a precision medicine-based approach so that in the future, improved treatment outcomes for children with relapsed and refractory disease can be realized. Our long-range goal is to optimize treatment of children with cancer by utilizing a precision medicine approach based on evaluation of the tumor and germline genomes to guide individualized therapies. In this effort, both focused and comprehensive deep sequencing of aggressive childhood cancers together with focused germline pharmacogenomics will be conducted. The objective of this proposal is to develop the foundation for an evidence-based strategy for developing precision medicine treatment regimens for children with relapsed malignancies. With the rapid improvement in efficiency and quality of genomic sequencing capabilities, an integrative sequencing approach to genomically characterize individual cancers to inform therapeutic decision- making for children with aggressive, often fatal malignancies is feasible. In parallel with the clinical component of this project, laboratory-based evaluation of patient-derived cell lines, and preclinical xenograft models developed from this same population of patients will allow broader evaluation of potential therapeutic options as well as discovery of novel targets via a comprehensive `omic' investigation. Our approach also provides an innovative opportunity to identify personalized, curative therapies for some of our most recalcitrant pediatric diseases. The research proposed in this project is innovative at the multiple levels critical not only for our pediatric cancer precision medicine program as well as pediatric patients everywhere. Pediatric cancer precision medicine is in its infancy in terms of developing a pipeline for rapid and accurate genomic analysis followed by team-based decisions regarding genome-directed therapeutic options. Our multidisciplinary project aims to provide cutting-edge, individualized therapeutic recommendations for children with cancer, for whom time to next therapeutic decision is crucial. The overall impact of this research is far reaching in improving the limited options that children with relapse cancers currently have. Information gained from these studies will have a significant positive impact by providing critical information for physicians to make informed decisions for safer and more effective use of drugs in children. The direct outcome of these multidisciplinary studies will be discovery of new biomarkers and predictive signatures that will increase the precision of treatment for life- threatening childhood cancers and minimize undesirable treatment-associated side effects.