Consensus molecular subtype 4 (CMS4)-targeted therapy in primary colon cancer: A proof-of-concept study
BackgroundMesenchymal Consensus Molecular Subtype 4 (CMS4) colon cancer is associated with poor prognosis and therapy resistance. In this proof-of-concept study, we assessed whether a rationally chosen drug could mitigate the distinguishing molecular features of primary CMS4 colon cancer.MethodsIn t...
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.969855/full |
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| author | Niek A. Peters Alexander Constantinides Inge Ubink Joyce van Kuik Haiko J. Bloemendal Haiko J. Bloemendal Joyce M. van Dodewaard Menno A. Brink Thijs P. Schwartz Martijn P.J.K. Lolkema Miangela M. Lacle Leon M. Moons Joost Geesing Wilhelmina M.U. van Grevenstein Jeanine M. L. Roodhart Jeanine M. L. Roodhart Miriam Koopman Sjoerd G. Elias Inne H.M. Borel Rinkes Inne H.M. Borel Rinkes Onno Kranenburg |
| author_facet | Niek A. Peters Alexander Constantinides Inge Ubink Joyce van Kuik Haiko J. Bloemendal Haiko J. Bloemendal Joyce M. van Dodewaard Menno A. Brink Thijs P. Schwartz Martijn P.J.K. Lolkema Miangela M. Lacle Leon M. Moons Joost Geesing Wilhelmina M.U. van Grevenstein Jeanine M. L. Roodhart Jeanine M. L. Roodhart Miriam Koopman Sjoerd G. Elias Inne H.M. Borel Rinkes Inne H.M. Borel Rinkes Onno Kranenburg |
| author_sort | Niek A. Peters |
| collection | DOAJ |
| description | BackgroundMesenchymal Consensus Molecular Subtype 4 (CMS4) colon cancer is associated with poor prognosis and therapy resistance. In this proof-of-concept study, we assessed whether a rationally chosen drug could mitigate the distinguishing molecular features of primary CMS4 colon cancer.MethodsIn the ImPACCT trial, informed consent was obtained for molecular subtyping at initial diagnosis of colon cancer using a validated RT-qPCR CMS4-test on three biopsies per tumor (Phase-1, n=69 patients), and for neoadjuvant CMS4-targeting therapy with imatinib (Phase-2, n=5). Pre- and post-treatment tumor biopsies were analyzed by RNA-sequencing and immunohistochemistry. Imatinib-induced gene expression changes were associated with molecular subtypes and survival in an independent cohort of 3232 primary colon cancer.ResultsThe CMS4-test classified 52/172 biopsies as CMS4 (30%). Five patients consented to imatinib treatment prior to surgery, yielding 15 pre- and 15 post-treatment samples for molecular analysis. Imatinib treatment caused significant suppression of mesenchymal genes and upregulation of genes encoding epithelial junctions. The gene expression changes induced by imatinib were associated with improved survival and a shift from CMS4 to CMS2.ConclusionImatinib may have value as a CMS-switching drug in primary colon cancer and induces a gene expression program that is associated with improved survival. |
| first_indexed | 2024-04-12T18:33:14Z |
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| last_indexed | 2024-04-12T18:33:14Z |
| publishDate | 2022-09-01 |
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| series | Frontiers in Oncology |
| spelling | doaj.art-aa2ea800e7be4277afea3b34814f26b92022-12-22T03:21:01ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-09-011210.3389/fonc.2022.969855969855Consensus molecular subtype 4 (CMS4)-targeted therapy in primary colon cancer: A proof-of-concept studyNiek A. Peters0Alexander Constantinides1Inge Ubink2Joyce van Kuik3Haiko J. Bloemendal4Haiko J. Bloemendal5Joyce M. van Dodewaard6Menno A. Brink7Thijs P. Schwartz8Martijn P.J.K. Lolkema9Miangela M. Lacle10Leon M. Moons11Joost Geesing12Wilhelmina M.U. van Grevenstein13Jeanine M. L. Roodhart14Jeanine M. L. Roodhart15Miriam Koopman16Sjoerd G. Elias17Inne H.M. Borel Rinkes18Inne H.M. Borel Rinkes19Onno Kranenburg20Lab Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsLab Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsLab Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsDepartment of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsDepartment of Internal Medicine, Meander Medical Center, Amersfoort, NetherlandsDepartment of Internal Medicine/Oncology, Radboud University Medical Center Nijmegen, Nijmegen, NetherlandsDepartment of Internal Medicine, Meander Medical Center, Amersfoort, NetherlandsDepartment of Gastroenterology, Meander Medical Center, Amersfoort, NetherlandsDepartment of Gastroenterology, Meander Medical Center, Amersfoort, NetherlandsDepartment of Medical Oncology, Erasmus Medical Center, Rotterdam, NetherlandsDepartment of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsDepartment of Gastroenterology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsDepartment of Gastroenterology, Diakonessenhuis, Utrecht, NetherlandsDepartment of Surgical Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsLab Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands0Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands0Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands1Julius Centre for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsLab Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsDepartment of Surgical Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsLab Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsBackgroundMesenchymal Consensus Molecular Subtype 4 (CMS4) colon cancer is associated with poor prognosis and therapy resistance. In this proof-of-concept study, we assessed whether a rationally chosen drug could mitigate the distinguishing molecular features of primary CMS4 colon cancer.MethodsIn the ImPACCT trial, informed consent was obtained for molecular subtyping at initial diagnosis of colon cancer using a validated RT-qPCR CMS4-test on three biopsies per tumor (Phase-1, n=69 patients), and for neoadjuvant CMS4-targeting therapy with imatinib (Phase-2, n=5). Pre- and post-treatment tumor biopsies were analyzed by RNA-sequencing and immunohistochemistry. Imatinib-induced gene expression changes were associated with molecular subtypes and survival in an independent cohort of 3232 primary colon cancer.ResultsThe CMS4-test classified 52/172 biopsies as CMS4 (30%). Five patients consented to imatinib treatment prior to surgery, yielding 15 pre- and 15 post-treatment samples for molecular analysis. Imatinib treatment caused significant suppression of mesenchymal genes and upregulation of genes encoding epithelial junctions. The gene expression changes induced by imatinib were associated with improved survival and a shift from CMS4 to CMS2.ConclusionImatinib may have value as a CMS-switching drug in primary colon cancer and induces a gene expression program that is associated with improved survival.https://www.frontiersin.org/articles/10.3389/fonc.2022.969855/fullcolorectal cancerconsensus molecular subtype 4imatinibImPACCTplatelet-derived growth factor receptor (PDGFR) |
| spellingShingle | Niek A. Peters Alexander Constantinides Inge Ubink Joyce van Kuik Haiko J. Bloemendal Haiko J. Bloemendal Joyce M. van Dodewaard Menno A. Brink Thijs P. Schwartz Martijn P.J.K. Lolkema Miangela M. Lacle Leon M. Moons Joost Geesing Wilhelmina M.U. van Grevenstein Jeanine M. L. Roodhart Jeanine M. L. Roodhart Miriam Koopman Sjoerd G. Elias Inne H.M. Borel Rinkes Inne H.M. Borel Rinkes Onno Kranenburg Consensus molecular subtype 4 (CMS4)-targeted therapy in primary colon cancer: A proof-of-concept study Frontiers in Oncology colorectal cancer consensus molecular subtype 4 imatinib ImPACCT platelet-derived growth factor receptor (PDGFR) |
| title | Consensus molecular subtype 4 (CMS4)-targeted therapy in primary colon cancer: A proof-of-concept study |
| title_full | Consensus molecular subtype 4 (CMS4)-targeted therapy in primary colon cancer: A proof-of-concept study |
| title_fullStr | Consensus molecular subtype 4 (CMS4)-targeted therapy in primary colon cancer: A proof-of-concept study |
| title_full_unstemmed | Consensus molecular subtype 4 (CMS4)-targeted therapy in primary colon cancer: A proof-of-concept study |
| title_short | Consensus molecular subtype 4 (CMS4)-targeted therapy in primary colon cancer: A proof-of-concept study |
| title_sort | consensus molecular subtype 4 cms4 targeted therapy in primary colon cancer a proof of concept study |
| topic | colorectal cancer consensus molecular subtype 4 imatinib ImPACCT platelet-derived growth factor receptor (PDGFR) |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.969855/full |
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