A Functional Precision Medicine Pipeline Combines Comparative Transcriptomics and Tumor Organoid Modeling to Identify Bespoke Treatment Strategies for Glioblastoma
Megan R. Reed,
A. Geoffrey Lyle,
Annick De Loose,
Leena Maddukuri,
Katrina Learned,
Holly C. Beale,
Ellen T. Kephart,
Allison Cheney,
Anouk van den Bout,
Madison P. Lee,
Kelsey N. Hundley,
Ashley M. Smith,
Teresa M. DesRochers,
Cecile Rose T. Vibat,
Murat Gokden,
Sofie Salama,
Christopher P. Wardell,
Robert L. Eoff,
Olena M. Vaske,
Analiz Rodriguez
Affiliations
Megan R. Reed
Department of Biochemistry, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
A. Geoffrey Lyle
Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA
Annick De Loose
Department of Neurosurgery, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Leena Maddukuri
Department of Biochemistry, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Katrina Learned
UC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA 95064, USA
Holly C. Beale
Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA
Ellen T. Kephart
UC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA 95064, USA
Allison Cheney
Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA
Anouk van den Bout
Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA
Madison P. Lee
Department of Neurosurgery, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Kelsey N. Hundley
Department of Neurosurgery, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Ashley M. Smith
KIYATEC Inc., Greenville, SC 29605, USA
Teresa M. DesRochers
KIYATEC Inc., Greenville, SC 29605, USA
Cecile Rose T. Vibat
KIYATEC Inc., Greenville, SC 29605, USA
Murat Gokden
Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Sofie Salama
Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA
Christopher P. Wardell
Department of Biomedical Informatics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Robert L. Eoff
Department of Biochemistry, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Olena M. Vaske
Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA
Analiz Rodriguez
Department of Neurosurgery, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
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.
