Proteomics and Personalized Patient-Derived Xenograft Models Identify Treatment Opportunities for a Progressive Malignancy Within a Clinically Actionable Timeframe and Change Care

Increased access to high-throughput DNA sequencing platforms has transformed the diagnostic landscape of pediatric malignancies by identifying and integrating actionable genomic or transcriptional features that refine diagnosis, classification, and treatment. Yet less than 10% of treated patients show a positive response and translating precision oncology data into feasible and effective therapies for hard-to-cure childhood, adolescent, and young adult malignancies remains a significant challenge. Combining the identification of therapeutic targets at the protein and pathway levels with demonstration of treatment response in personalized models holds great promise. Here we present the case for combining proteomics with patient-derived xenograft (PDX) models to identify personalized treatment options that were not apparent at genomic and transcriptomic levels. Proteome analysis with immunohistochemistry (IHC) validation of formalin-fixed paraffin-embedded sections from an adolescent with primary and metastatic spindle epithelial tumor with thymus-like elements (SETTLE) was completed within two weeks of biopsy. The results identified an elevated protein level of SHMT2 as a possible target for therapy with the commercially available anti-depressant sertraline. Within 2 months and ahead of a molecular tumor board, we confirmed a positive drug response in a personalized chick chorioallantoic membrane (CAM) model of the SETTLE tumor (CAM-PDX). Following the failure of cytotoxic chemotherapy and second-line therapy, a treatment of sertraline was initiated for the patient. After 3 months of sertraline treatment the patient showed decreased tumor growth rates, albeit with clinically progressive disease. Significance: Overall, we demonstrate that proteomics and fast-track personalized xenograft models can provide supportive pre-clinical data in a clinically meaningful timeframe to support medical decision-making and impact the 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Data and/or materials used for this research were made available by the PRecision Oncology For Young peopLE (PROFYLE) program. PROFYLE has been supported by funds from many funders including Alberta Cancer Foundation, Alberta Childrens Hospital Foundation, BC Cancer Foundation, BC Childrens Hospital Foundation, Childhood Cancer Canada, Kids Cancer Care Foundation and Terry Fox Research Institute. This work was supported by the BC Childrens Hospital Foundation through the Better Responses through Avatars and Evidence (BRAvE) Initiative. Salary support was provided by the Michael Cuccione Foundation MCF (C.J.L., G.S.D.R., C.A.M., P.F.L., V.G.), the Canada Research Chairs Program (CRC-RS 950-230867, P.F.L.), the Canadian Institutes of Health Research (C.A.M., P.F.L.), the Michael Smith Foundation for Health Research Scholar Program (16442, P.F.L.), MITACS (T.A.B., G.B.) and the University of British Columbia (E.K.E.). Project support for J.A.C. and D.L.S. was provided by The Alberta Cancer Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Children and Womens Research Ethics Board of the University of British Columbia gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes To maintain the patients and familys privacy in this study of a single case the raw data is not made available at this point. Release of the raw data as part of an aggregated patient cohort is in preparation.