A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma
Summary: Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. The disease presents with a complex spectrum of genomic aberrations, but the pharmacological consequences of these aberrations are partly unknown. Here, we report an integrated pharmacogenomic analysis of 100 patien...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-07-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720308780 |
| _version_ | 1811222758148800512 |
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| author | Patrik Johansson Cecilia Krona Soumi Kundu Milena Doroszko Sathishkumar Baskaran Linnéa Schmidt Claire Vinel Elin Almstedt Ramy Elgendy Ludmila Elfineh Caroline Gallant Sara Lundsten Fernando J. Ferrer Gago Aleksi Hakkarainen Petra Sipilä Maria Häggblad Ulf Martens Bo Lundgren Melanie M. Frigault David P. Lane Fredrik J. Swartling Lene Uhrbom Marika Nestor Silvia Marino Sven Nelander |
| author_facet | Patrik Johansson Cecilia Krona Soumi Kundu Milena Doroszko Sathishkumar Baskaran Linnéa Schmidt Claire Vinel Elin Almstedt Ramy Elgendy Ludmila Elfineh Caroline Gallant Sara Lundsten Fernando J. Ferrer Gago Aleksi Hakkarainen Petra Sipilä Maria Häggblad Ulf Martens Bo Lundgren Melanie M. Frigault David P. Lane Fredrik J. Swartling Lene Uhrbom Marika Nestor Silvia Marino Sven Nelander |
| author_sort | Patrik Johansson |
| collection | DOAJ |
| description | Summary: Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. The disease presents with a complex spectrum of genomic aberrations, but the pharmacological consequences of these aberrations are partly unknown. Here, we report an integrated pharmacogenomic analysis of 100 patient-derived GBM cell cultures from the human glioma cell culture (HGCC) cohort. Exploring 1,544 drugs, we find that GBM has two main pharmacological subgroups, marked by differential response to proteasome inhibitors and mutually exclusive aberrations in TP53 and CDKN2A/B. We confirm this trend in cell and in xenotransplantation models, and identify both Bcl-2 family inhibitors and p53 activators as potentiators of proteasome inhibitors in GBM cells. We can further predict the responses of individual cell cultures to several existing drug classes, presenting opportunities for drug repurposing and design of stratified trials. Our functionally profiled biobank provides a valuable resource for the discovery of new treatments for GBM. |
| first_indexed | 2024-04-12T08:20:17Z |
| format | Article |
| id | doaj.art-cc573e6ed9f44191ba0a80782a5d717e |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-12T08:20:17Z |
| publishDate | 2020-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-cc573e6ed9f44191ba0a80782a5d717e2022-12-22T03:40:36ZengElsevierCell Reports2211-12472020-07-01322107897A Patient-Derived Cell Atlas Informs Precision Targeting of GlioblastomaPatrik Johansson0Cecilia Krona1Soumi Kundu2Milena Doroszko3Sathishkumar Baskaran4Linnéa Schmidt5Claire Vinel6Elin Almstedt7Ramy Elgendy8Ludmila Elfineh9Caroline Gallant10Sara Lundsten11Fernando J. Ferrer Gago12Aleksi Hakkarainen13Petra Sipilä14Maria Häggblad15Ulf Martens16Bo Lundgren17Melanie M. Frigault18David P. Lane19Fredrik J. Swartling20Lene Uhrbom21Marika Nestor22Silvia Marino23Sven Nelander24Department of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, SwedenDepartment of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, SwedenDepartment of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, SwedenDepartment of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, SwedenDepartment of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, SwedenDepartment of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, SwedenBlizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UKDepartment of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, SwedenDepartment of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, SwedenDepartment of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, SwedenDepartment of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, SwedenDepartment of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, SwedenLaboratory, Agency for Science, Technology and Research (A∗STAR), Singapore 138648, SingaporeInstitute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, 20500 Turku, FinlandInstitute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, 20500 Turku, FinlandDepartment of Biochemistry and Biophysics, SciLifeLab, Stockholm University, 104 05 Stockholm, SwedenDepartment of Biochemistry and Biophysics, SciLifeLab, Stockholm University, 104 05 Stockholm, SwedenDepartment of Biochemistry and Biophysics, SciLifeLab, Stockholm University, 104 05 Stockholm, SwedenAstraZeneca Oncology, Waltham, MA 02451, USALaboratory, Agency for Science, Technology and Research (A∗STAR), Singapore 138648, Singapore; Dept of Microbiology, Tumor and Cell Biology, Science for Life Laboratory, Karolinska Institutet, 17177 Stockholm, SwedenDepartment of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, SwedenDepartment of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, SwedenDepartment of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, SwedenBlizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UKDepartment of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, Sweden; Corresponding authorSummary: Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. The disease presents with a complex spectrum of genomic aberrations, but the pharmacological consequences of these aberrations are partly unknown. Here, we report an integrated pharmacogenomic analysis of 100 patient-derived GBM cell cultures from the human glioma cell culture (HGCC) cohort. Exploring 1,544 drugs, we find that GBM has two main pharmacological subgroups, marked by differential response to proteasome inhibitors and mutually exclusive aberrations in TP53 and CDKN2A/B. We confirm this trend in cell and in xenotransplantation models, and identify both Bcl-2 family inhibitors and p53 activators as potentiators of proteasome inhibitors in GBM cells. We can further predict the responses of individual cell cultures to several existing drug classes, presenting opportunities for drug repurposing and design of stratified trials. Our functionally profiled biobank provides a valuable resource for the discovery of new treatments for GBM.http://www.sciencedirect.com/science/article/pii/S2211124720308780biobankcombination therapydata integrationglioblastomamulti-omicsp53 reactivators |
| spellingShingle | Patrik Johansson Cecilia Krona Soumi Kundu Milena Doroszko Sathishkumar Baskaran Linnéa Schmidt Claire Vinel Elin Almstedt Ramy Elgendy Ludmila Elfineh Caroline Gallant Sara Lundsten Fernando J. Ferrer Gago Aleksi Hakkarainen Petra Sipilä Maria Häggblad Ulf Martens Bo Lundgren Melanie M. Frigault David P. Lane Fredrik J. Swartling Lene Uhrbom Marika Nestor Silvia Marino Sven Nelander A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma Cell Reports biobank combination therapy data integration glioblastoma multi-omics p53 reactivators |
| title | A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma |
| title_full | A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma |
| title_fullStr | A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma |
| title_full_unstemmed | A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma |
| title_short | A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma |
| title_sort | patient derived cell atlas informs precision targeting of glioblastoma |
| topic | biobank combination therapy data integration glioblastoma multi-omics p53 reactivators |
| url | http://www.sciencedirect.com/science/article/pii/S2211124720308780 |
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