A New Personalized Medicine Model for High-Risk Pediatric Sarcomas

ABSTRACT Pediatric sarcomas, including osteosarcoma, Ewing’s sarcoma, and rhabdomyosarcoma, are high- risk cancers with survival rates ~30% upon tumor metastasis or post-treatment relapse. A key obstacle to effective treatment is the varied nature of these tumors. They differ at the molecular level between patients and have pronounced intra-tumoral heterogeneity, meaning that different cells within a single patient’s tumor can have distinct molecular and functional profiles. This complexity makes the development of personalized treatments difficult. Currently, salvage therapies are administered after primary treatments fail, and often resort to a trial-and-error approach. Trying one treatment after another in the hopes of findings a drug that is effective can inflict considerable physiological and psychological burdens on patients and their families. We seek to address this issue by developing zebrafish avatar models as tools for predicting patient-specific treatment outcomes. Zebrafish provide a robust platform for precision medicine approaches. We have previously found they will readily engraft any cancer type, including patient-derived cells, and drug treatments in zebrafish xenografts are typically completed in 3 days. This means that the turn-around time, from patient sample collection to a functional report on drug responsiveness for that tumor, can be completed in as little as a week. Our study is structured around two aims: 1) Evaluate the conservation of a tumor’s molecular and functional characteristics between patient and their zebrafish avatars, and 2) Assess the accuracy of zebrafish avatar models in mirroring patient treatment outcomes, such as drug response, remission, and recurrence. Ultimately, we hope to use this model to complement to current clinical approaches and overcome the limitations of molecular profiling by providing a rapid functional readout of drug response. Our approach could potentially help predict relapse, minimize treatment side-effects, and save time wasted on ineffective treatments, leading to better overall outcomes for children with sarcoma.