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

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 p...

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Autores principales: Reed, Megan R., Lyle, A. Geoffrey, De Loose, Annick, Maddukuri, Leena, Learned, Katrina, Beale, Holly C., Kephart, Ellen T., Cheney, Allison, van den Bout, Anouk, Lee, Madison P., Hundley, Kelsey N., Smith, Ashley M., DesRochers, Teresa M., Vibat, Cecile Rose T., Gokden, Murat, Salama, Sofie, Wardell, Christopher P., Eoff, Robert L., Vaske, Olena M., Rodriguez, Analiz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699481/
https://www.ncbi.nlm.nih.gov/pubmed/34943910
http://dx.doi.org/10.3390/cells10123400
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author Reed, Megan R.
Lyle, A. Geoffrey
De Loose, Annick
Maddukuri, Leena
Learned, Katrina
Beale, Holly C.
Kephart, Ellen T.
Cheney, Allison
van den Bout, Anouk
Lee, Madison P.
Hundley, Kelsey N.
Smith, Ashley M.
DesRochers, Teresa M.
Vibat, Cecile Rose T.
Gokden, Murat
Salama, Sofie
Wardell, Christopher P.
Eoff, Robert L.
Vaske, Olena M.
Rodriguez, Analiz
author_facet Reed, Megan R.
Lyle, A. Geoffrey
De Loose, Annick
Maddukuri, Leena
Learned, Katrina
Beale, Holly C.
Kephart, Ellen T.
Cheney, Allison
van den Bout, Anouk
Lee, Madison P.
Hundley, Kelsey N.
Smith, Ashley M.
DesRochers, Teresa M.
Vibat, Cecile Rose T.
Gokden, Murat
Salama, Sofie
Wardell, Christopher P.
Eoff, Robert L.
Vaske, Olena M.
Rodriguez, Analiz
author_sort Reed, Megan R.
collection PubMed
description 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.
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spelling pubmed-86994812021-12-24 A Functional Precision Medicine Pipeline Combines Comparative Transcriptomics and Tumor Organoid Modeling to Identify Bespoke Treatment Strategies for Glioblastoma Reed, Megan R. Lyle, A. Geoffrey De Loose, Annick Maddukuri, Leena Learned, Katrina Beale, Holly C. Kephart, Ellen T. Cheney, Allison van den Bout, Anouk Lee, Madison P. Hundley, Kelsey N. Smith, Ashley M. DesRochers, Teresa M. Vibat, Cecile Rose T. Gokden, Murat Salama, Sofie Wardell, Christopher P. Eoff, Robert L. Vaske, Olena M. Rodriguez, Analiz Cells Article 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. MDPI 2021-12-02 /pmc/articles/PMC8699481/ /pubmed/34943910 http://dx.doi.org/10.3390/cells10123400 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Reed, Megan R.
Lyle, A. Geoffrey
De Loose, Annick
Maddukuri, Leena
Learned, Katrina
Beale, Holly C.
Kephart, Ellen T.
Cheney, Allison
van den Bout, Anouk
Lee, Madison P.
Hundley, Kelsey N.
Smith, Ashley M.
DesRochers, Teresa M.
Vibat, Cecile Rose T.
Gokden, Murat
Salama, Sofie
Wardell, Christopher P.
Eoff, Robert L.
Vaske, Olena M.
Rodriguez, Analiz
A Functional Precision Medicine Pipeline Combines Comparative Transcriptomics and Tumor Organoid Modeling to Identify Bespoke Treatment Strategies for Glioblastoma
title A Functional Precision Medicine Pipeline Combines Comparative Transcriptomics and Tumor Organoid Modeling to Identify Bespoke Treatment Strategies for Glioblastoma
title_full A Functional Precision Medicine Pipeline Combines Comparative Transcriptomics and Tumor Organoid Modeling to Identify Bespoke Treatment Strategies for Glioblastoma
title_fullStr A Functional Precision Medicine Pipeline Combines Comparative Transcriptomics and Tumor Organoid Modeling to Identify Bespoke Treatment Strategies for Glioblastoma
title_full_unstemmed A Functional Precision Medicine Pipeline Combines Comparative Transcriptomics and Tumor Organoid Modeling to Identify Bespoke Treatment Strategies for Glioblastoma
title_short A Functional Precision Medicine Pipeline Combines Comparative Transcriptomics and Tumor Organoid Modeling to Identify Bespoke Treatment Strategies for Glioblastoma
title_sort functional precision medicine pipeline combines comparative transcriptomics and tumor organoid modeling to identify bespoke treatment strategies for glioblastoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699481/
https://www.ncbi.nlm.nih.gov/pubmed/34943910
http://dx.doi.org/10.3390/cells10123400
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