A Functional Precision Medicine Pipeline Combines Comparative Transcriptomics and Tumor Organoid Modeling to Identify Bespoke Treatment Strategies for Glioblastoma

Autor: Christopher P. Wardell, Robert L. Eoff, Annick De Loose, Sofie R. Salama, Anouk van den Bout, Teresa M. DesRochers, A. Geoffrey Lyle, Murat Gokden, Madison P Lee, Kelsey Hundley, Analiz Rodriguez, Allison Cheney, Katrina Learned, Leena Maddukuri, Olena M. Vaske, Megan R. Reed, Holly C. Beale, Cecile Rose T. Vibat, Ashley M. Smith, Ellen Kephart
Rok vydání: 2021
Předmět:
Zdroj: Cells, Vol 10, Iss 3400, p 3400 (2021)
Cells
Cells; Volume 10; Issue 12; Pages: 3400
ISSN: 2073-4409
DOI: 10.3390/cells10123400
Popis: Li Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in TP53. TP53 is the most common mutated gene in human cancer, occurring in 30–50% of glioblastomas (GBM). Here, we highlight a precision medicine platform to identify potential targets for a GBM patient with LFS. We used a comparative transcriptomics approach to identify genes that are uniquely overexpressed in the LFS GBM patient relative to a cancer compendium of 12,747 tumor RNA sequencing data sets, including 200 GBMs. STAT1 and STAT2 were identified as being significantly overexpressed in the LFS patient, indicating ruxolitinib, a Janus kinase 1 and 2 inhibitors, as a potential therapy. The LFS patient had the highest level of STAT1 and STAT2 expression in an institutional high-grade glioma cohort of 45 patients, further supporting the cancer compendium results. To empirically validate the comparative transcriptomics pipeline, we used a combination of adherent and organoid cell culture techniques, including ex vivo patient-derived organoids (PDOs) from four patient-derived cell lines, including the LFS patient. STAT1 and STAT2 expression levels in the four patient-derived cells correlated with levels identified in the respective parent tumors. In both adherent and organoid cultures, cells from the LFS patient were among the most sensitive to ruxolitinib compared to patient-derived cells with lower STAT1 and STAT2 expression levels. A spheroid-based drug screening assay (3D-PREDICT) was performed and used to identify further therapeutic targets. Two targeted therapies were selected for the patient of interest and resulted in radiographic disease stability. This manuscript supports the use of comparative transcriptomics to identify personalized therapeutic targets in a functional precision medicine platform for malignant brain tumors.
Databáze: OpenAIRE
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