Genomics has transformed the diagnostic landscape of pediatric malignancies by identifying and integrating actionable features that refine diagnosis, classification, and treatment. Yet, translating precision oncology data into effective therapies for hard-to-cure childhood, adolescent, and young adult malignancies remains a significant challenge. We present the case for combining proteomics with patient-derived xenograft models to identify personalized treatment for an adolescent with primary and metastatic spindle epithelial tumor with thymus-like elements (SETTLE). Within two weeks of biopsy, proteomics identified elevated SHMT2 as a target for therapy with the anti-depressant sertraline. Drug response was confirmed within two months using a personalized chicken chorioallantoic membrane model of the patient's SETTLE tumor. Following failure of cytotoxic chemotherapy and second-line therapy, the patient received sertraline treatment and showed decreased tumor growth rates, albeit with clinically progressive disease. We demonstrate that proteomics and fast-track xenograft models provide supportive pre-clinical data in a clinically meaningful timeframe to impact clinical practice. By this, we show that proteome-guided and functional precision oncology are feasible and valuable complements to the current genome-driven precision oncology practices.