Proteomics and personalized PDX models identify treatment for a progressive malignancy within an actionable timeframe
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.
Authors
- Verena Goebeler (ORCID: https://orcid.org/0000-0002-6847-3141)
- Pascal Leclair (ORCID: https://orcid.org/0000-0002-0791-7028)
- Chinten James Lim (ORCID: https://orcid.org/0000-0001-6381-7585)
- Donna L. Senger (ORCID: https://orcid.org/0000-0003-2403-3395)
- Caron Strahlendorf (ORCID: https://orcid.org/0000-0001-9940-4926)
- Jonathan W. Bush (ORCID: https://orcid.org/0000-0001-9432-2390)
- Philipp F. Lange (ORCID: https://orcid.org/0000-0003-1171-5864)
- Rebecca J. Deyell (ORCID: https://orcid.org/0000-0003-3315-4383)
- Jason N. Berman (ORCID: https://orcid.org/0000-0002-4053-6067)
- Nadine Azzam (ORCID: https://orcid.org/0009-0008-6241-4029)
- Nicole Melong (ORCID: https://orcid.org/0000-0002-0429-0944)
- Andrew J. Mungall (ORCID: https://orcid.org/0000-0002-0905-2742)
- Georgina D. Barnabas
- Enes K. Ergin (ORCID: https://orcid.org/0000-0001-9810-7399)
- Christopher A. Maxwell (ORCID: https://orcid.org/0000-0002-0713-7136)
- Gregor S. D. Reid (ORCID: https://orcid.org/0000-0002-7567-3424)
- Jennifer A. Chan (ORCID: https://orcid.org/0000-0001-9798-1551)
- Martin Hirst (ORCID: https://orcid.org/0000-0001-9136-9054)
- Christopher W. Anderson (ORCID: https://orcid.org/0000-0002-0801-5341)
- Agustina Conrrero
- Steven J.M. Jones (ORCID: https://orcid.org/0000-0003-3394-2208)
- Karen Mungall (ORCID: https://orcid.org/0000-0002-9092-4391)
- Yaoqing Shen (ORCID: https://orcid.org/0000-0002-7978-0008)
- Seohee An
- Seth J. Parker (ORCID: https://orcid.org/0000-0001-7971-8848)
- Tariq Ahmad Bhat (ORCID: https://orcid.org/0000-0002-1372-4548)
- Alexis Gom
Institutions
- University of British Columbia Hospital (CA)
- BC Cancer Agency (CA)
- University of British Columbia (CA)
- University of Ottawa (CA)
- University of Calgary (CA)
- Children's Hospital of Eastern Ontario (CA)
- McGill University Health Centre (CA)
- Jewish General Hospital (CA)
- Alberta Children's Hospital (CA)
- Canada's Michael Smith Genome Sciences Centre (CA)
- BC Children's Hospital (CA)
- McGill University (CA)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1038/s44321-025-00212-8
- Citations
- 2
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Children's Hospital Foundation
- BC Children’s Hospital Foundation
- BC Children's Hospital
- Alberta Cancer Foundation
- Michael Smith Health Research BC
- Canada Research Chairs
- Mitacs
- University of British Columbia
- Canadian Institutes of Health Research