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

Autor: Reed MR; Department of Biochemistry, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.; Department of Neurosurgery, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA., Lyle AG; Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA.; UC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA 95064, USA., De Loose A; Department of Neurosurgery, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA., Maddukuri L; Department of Biochemistry, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA., Learned K; UC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA 95064, USA., Beale HC; Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA.; UC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA 95064, USA., Kephart ET; UC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA 95064, USA., Cheney A; Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA.; UC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA 95064, USA., van den Bout A; Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA.; UC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA 95064, USA., Lee MP; Department of Neurosurgery, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA., Hundley KN; Department of Neurosurgery, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA., Smith AM; KIYATEC Inc., Greenville, SC 29605, USA., DesRochers TM; KIYATEC Inc., Greenville, SC 29605, USA., Vibat CRT; KIYATEC Inc., Greenville, SC 29605, USA., Gokden M; Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA., Salama S; Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA.; Howard Hughes Medical Institute, University of California Santa Cruz, Santa Cruz, CA 95064, USA., Wardell CP; Department of Biomedical Informatics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA., Eoff RL; Department of Biochemistry, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA., Vaske OM; Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA., Rodriguez A; Department of Neurosurgery, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Jazyk: angličtina
Zdroj: Cells [Cells] 2021 Dec 02; Vol. 10 (12). Date of Electronic Publication: 2021 Dec 02.
DOI: 10.3390/cells10123400
Abstrakt: 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: MEDLINE
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