Platform combining statistical modeling and patient-derived organoids to facilitate personalized treatment of colorectal carcinoma
Abstract Background We propose a new approach for designing personalized treatment for colorectal cancer (CRC) patients, by combining ex vivo organoid efficacy testing with mathematical modeling of the results. Methods The validated phenotypic approach called Therapeutically Guided Multidrug Optimiz...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-04-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-023-02650-z |
| _version_ | 1797849833093988352 |
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| author | George M. Ramzy Maxim Norkin Thibaud Koessler Lionel Voirol Mathieu Tihy Dina Hany Thomas McKee Frédéric Ris Nicolas Buchs Mylène Docquier Christian Toso Laura Rubbia-Brandt Gaetan Bakalli Stéphane Guerrier Joerg Huelsken Patrycja Nowak-Sliwinska |
| author_facet | George M. Ramzy Maxim Norkin Thibaud Koessler Lionel Voirol Mathieu Tihy Dina Hany Thomas McKee Frédéric Ris Nicolas Buchs Mylène Docquier Christian Toso Laura Rubbia-Brandt Gaetan Bakalli Stéphane Guerrier Joerg Huelsken Patrycja Nowak-Sliwinska |
| author_sort | George M. Ramzy |
| collection | DOAJ |
| description | Abstract Background We propose a new approach for designing personalized treatment for colorectal cancer (CRC) patients, by combining ex vivo organoid efficacy testing with mathematical modeling of the results. Methods The validated phenotypic approach called Therapeutically Guided Multidrug Optimization (TGMO) was used to identify four low-dose synergistic optimized drug combinations (ODC) in 3D human CRC models of cells that are either sensitive or resistant to first-line CRC chemotherapy (FOLFOXIRI). Our findings were obtained using second order linear regression and adaptive lasso. Results The activity of all ODCs was validated on patient-derived organoids (PDO) from cases with either primary or metastatic CRC. The CRC material was molecularly characterized using whole-exome sequencing and RNAseq. In PDO from patients with liver metastases (stage IV) identified as CMS4/CRIS-A, our ODCs consisting of regorafenib [1 mM], vemurafenib [11 mM], palbociclib [1 mM] and lapatinib [0.5 mM] inhibited cell viability up to 88%, which significantly outperforms FOLFOXIRI administered at clinical doses. Furthermore, we identified patient-specific TGMO-based ODCs that outperform the efficacy of the current chemotherapy standard of care, FOLFOXIRI. Conclusions Our approach allows the optimization of patient-tailored synergistic multi-drug combinations within a clinically relevant timeframe. Graphical Abstract |
| first_indexed | 2024-04-09T18:50:34Z |
| format | Article |
| id | doaj.art-60bf5c4478c549e8812684c5f9a09d4e |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-09T18:50:34Z |
| publishDate | 2023-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-60bf5c4478c549e8812684c5f9a09d4e2023-04-09T11:29:54ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662023-04-0142111710.1186/s13046-023-02650-zPlatform combining statistical modeling and patient-derived organoids to facilitate personalized treatment of colorectal carcinomaGeorge M. Ramzy0Maxim Norkin1Thibaud Koessler2Lionel Voirol3Mathieu Tihy4Dina Hany5Thomas McKee6Frédéric Ris7Nicolas Buchs8Mylène Docquier9Christian Toso10Laura Rubbia-Brandt11Gaetan Bakalli12Stéphane Guerrier13Joerg Huelsken14Patrycja Nowak-Sliwinska15Molecular Pharmacology Group, School of Pharmaceutical Sciences, University of GenevaSwiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne-(EPFL-SV)Department of Oncology, Geneva University HospitalsResearch Center for Statistics, Geneva School of Economics and Management, University of GenevaDivision of Clinical Pathology, Diagnostic Department, University Hospitals of Geneva (HUG)Molecular Pharmacology Group, School of Pharmaceutical Sciences, University of GenevaDivision of Clinical Pathology, Diagnostic Department, University Hospitals of Geneva (HUG)Translational Department of Digestive and Transplant Surgery, Geneva University Hospitals and Faculty of MedicineTranslational Department of Digestive and Transplant Surgery, Geneva University Hospitals and Faculty of MedicineiGE3 Genomics Platform, University of GenevaDepartment of Visceral Surgery, Geneva University HospitalDivision of Clinical Pathology, Diagnostic Department, University Hospitals of Geneva (HUG)EMLYON Business School, Artificial Intelligence in Management InstituteInstitute of Pharmaceutical Sciences of Western Switzerland, University of GenevaSwiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne-(EPFL-SV)Molecular Pharmacology Group, School of Pharmaceutical Sciences, University of GenevaAbstract Background We propose a new approach for designing personalized treatment for colorectal cancer (CRC) patients, by combining ex vivo organoid efficacy testing with mathematical modeling of the results. Methods The validated phenotypic approach called Therapeutically Guided Multidrug Optimization (TGMO) was used to identify four low-dose synergistic optimized drug combinations (ODC) in 3D human CRC models of cells that are either sensitive or resistant to first-line CRC chemotherapy (FOLFOXIRI). Our findings were obtained using second order linear regression and adaptive lasso. Results The activity of all ODCs was validated on patient-derived organoids (PDO) from cases with either primary or metastatic CRC. The CRC material was molecularly characterized using whole-exome sequencing and RNAseq. In PDO from patients with liver metastases (stage IV) identified as CMS4/CRIS-A, our ODCs consisting of regorafenib [1 mM], vemurafenib [11 mM], palbociclib [1 mM] and lapatinib [0.5 mM] inhibited cell viability up to 88%, which significantly outperforms FOLFOXIRI administered at clinical doses. Furthermore, we identified patient-specific TGMO-based ODCs that outperform the efficacy of the current chemotherapy standard of care, FOLFOXIRI. Conclusions Our approach allows the optimization of patient-tailored synergistic multi-drug combinations within a clinically relevant timeframe. Graphical Abstracthttps://doi.org/10.1186/s13046-023-02650-zDrug-drug interactionDrug resistanceMultidrug combinationOrganoidPhenotypic screenSynergy |
| spellingShingle | George M. Ramzy Maxim Norkin Thibaud Koessler Lionel Voirol Mathieu Tihy Dina Hany Thomas McKee Frédéric Ris Nicolas Buchs Mylène Docquier Christian Toso Laura Rubbia-Brandt Gaetan Bakalli Stéphane Guerrier Joerg Huelsken Patrycja Nowak-Sliwinska Platform combining statistical modeling and patient-derived organoids to facilitate personalized treatment of colorectal carcinoma Journal of Experimental & Clinical Cancer Research Drug-drug interaction Drug resistance Multidrug combination Organoid Phenotypic screen Synergy |
| title | Platform combining statistical modeling and patient-derived organoids to facilitate personalized treatment of colorectal carcinoma |
| title_full | Platform combining statistical modeling and patient-derived organoids to facilitate personalized treatment of colorectal carcinoma |
| title_fullStr | Platform combining statistical modeling and patient-derived organoids to facilitate personalized treatment of colorectal carcinoma |
| title_full_unstemmed | Platform combining statistical modeling and patient-derived organoids to facilitate personalized treatment of colorectal carcinoma |
| title_short | Platform combining statistical modeling and patient-derived organoids to facilitate personalized treatment of colorectal carcinoma |
| title_sort | platform combining statistical modeling and patient derived organoids to facilitate personalized treatment of colorectal carcinoma |
| topic | Drug-drug interaction Drug resistance Multidrug combination Organoid Phenotypic screen Synergy |
| url | https://doi.org/10.1186/s13046-023-02650-z |
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