Optimized low‐dose combinatorial drug treatment boosts selectivity and efficacy of colorectal carcinoma treatment
The current standard of care for colorectal cancer (CRC) is a combination of chemotherapeutics, often supplemented with targeted biological drugs. An urgent need exists for improved drug efficacy and minimized side effects, especially at late‐stage disease. We employed the phenotypically driven ther...
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Wiley
2020-11-01
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Series: | Molecular Oncology |
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Online Access: | https://doi.org/10.1002/1878-0261.12797 |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Marloes Zoetemelk George M. Ramzy Magdalena Rausch Thibaud Koessler Judy R. vanBeijnum Andrea Weiss Valentin Mieville Sander R. Piersma Richard R. deHaas Céline Delucinge‐Vivier Axel Andres Christian Toso Alexander A. Henneman Simone Ragusa Tatiana V. Petrova Mylène Docquier Thomas A. McKee Connie R. Jimenez Youssef Daali Arjan W. Griffioen Laura Rubbia‐Brandt Pierre‐Yves Dietrich Patrycja Nowak‐Sliwinska |
spellingShingle |
Marloes Zoetemelk George M. Ramzy Magdalena Rausch Thibaud Koessler Judy R. vanBeijnum Andrea Weiss Valentin Mieville Sander R. Piersma Richard R. deHaas Céline Delucinge‐Vivier Axel Andres Christian Toso Alexander A. Henneman Simone Ragusa Tatiana V. Petrova Mylène Docquier Thomas A. McKee Connie R. Jimenez Youssef Daali Arjan W. Griffioen Laura Rubbia‐Brandt Pierre‐Yves Dietrich Patrycja Nowak‐Sliwinska Optimized low‐dose combinatorial drug treatment boosts selectivity and efficacy of colorectal carcinoma treatment Molecular Oncology colorectal carcinoma combination treatment drug–drug interactions drug–target interactions phosphoproteomics synergy |
author_facet |
Marloes Zoetemelk George M. Ramzy Magdalena Rausch Thibaud Koessler Judy R. vanBeijnum Andrea Weiss Valentin Mieville Sander R. Piersma Richard R. deHaas Céline Delucinge‐Vivier Axel Andres Christian Toso Alexander A. Henneman Simone Ragusa Tatiana V. Petrova Mylène Docquier Thomas A. McKee Connie R. Jimenez Youssef Daali Arjan W. Griffioen Laura Rubbia‐Brandt Pierre‐Yves Dietrich Patrycja Nowak‐Sliwinska |
author_sort |
Marloes Zoetemelk |
title |
Optimized low‐dose combinatorial drug treatment boosts selectivity and efficacy of colorectal carcinoma treatment |
title_short |
Optimized low‐dose combinatorial drug treatment boosts selectivity and efficacy of colorectal carcinoma treatment |
title_full |
Optimized low‐dose combinatorial drug treatment boosts selectivity and efficacy of colorectal carcinoma treatment |
title_fullStr |
Optimized low‐dose combinatorial drug treatment boosts selectivity and efficacy of colorectal carcinoma treatment |
title_full_unstemmed |
Optimized low‐dose combinatorial drug treatment boosts selectivity and efficacy of colorectal carcinoma treatment |
title_sort |
optimized low‐dose combinatorial drug treatment boosts selectivity and efficacy of colorectal carcinoma treatment |
publisher |
Wiley |
series |
Molecular Oncology |
issn |
1574-7891 1878-0261 |
publishDate |
2020-11-01 |
description |
The current standard of care for colorectal cancer (CRC) is a combination of chemotherapeutics, often supplemented with targeted biological drugs. An urgent need exists for improved drug efficacy and minimized side effects, especially at late‐stage disease. We employed the phenotypically driven therapeutically guided multidrug optimization (TGMO) technology to identify optimized drug combinations (ODCs) in CRC. We identified low‐dose synergistic and selective ODCs for a panel of six human CRC cell lines also active in heterotypic 3D co‐culture models. Transcriptome sequencing and phosphoproteome analyses showed that the mechanisms of action of these ODCs converged toward MAP kinase signaling and cell cycle inhibition. Two cell‐specific ODCs were translated to in vivo mouse models. The ODCs reduced tumor growth by ~80%, outperforming standard chemotherapy (FOLFOX). No toxicity was observed for the ODCs, while significant side effects were induced in the group treated with FOLFOX therapy. Identified ODCs demonstrated significantly enhanced bioavailability of the individual components. Finally, ODCs were also active in primary cells from CRC patient tumor tissues. Taken together, we show that the TGMO technology efficiently identifies selective and potent low‐dose drug combinations, optimized regardless of tumor mutation status, outperforming conventional chemotherapy. |
topic |
colorectal carcinoma combination treatment drug–drug interactions drug–target interactions phosphoproteomics synergy |
url |
https://doi.org/10.1002/1878-0261.12797 |
work_keys_str_mv |
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doaj-95a558b6cae1422989a521f96cb740012020-11-25T04:07:17ZengWileyMolecular Oncology1574-78911878-02612020-11-0114112894291910.1002/1878-0261.12797Optimized low‐dose combinatorial drug treatment boosts selectivity and efficacy of colorectal carcinoma treatmentMarloes Zoetemelk0George M. Ramzy1Magdalena Rausch2Thibaud Koessler3Judy R. vanBeijnum4Andrea Weiss5Valentin Mieville6Sander R. Piersma7Richard R. deHaas8Céline Delucinge‐Vivier9Axel Andres10Christian Toso11Alexander A. Henneman12Simone Ragusa13Tatiana V. Petrova14Mylène Docquier15Thomas A. McKee16Connie R. Jimenez17Youssef Daali18Arjan W. Griffioen19Laura Rubbia‐Brandt20Pierre‐Yves Dietrich21Patrycja Nowak‐Sliwinska22Molecular Pharmacology Group School of Pharmaceutical Sciences University of Geneva SwitzerlandMolecular Pharmacology Group School of Pharmaceutical Sciences University of Geneva SwitzerlandMolecular Pharmacology Group School of Pharmaceutical Sciences University of Geneva SwitzerlandDepartment of Oncology Geneva University Hospitals and Faculty of Medicine SwitzerlandAngiogenesis Laboratory Department of Medical Oncology Cancer Center Amsterdam Amsterdam UMC‐location VUmc VU University Amsterdam The NetherlandsMolecular Pharmacology Group School of Pharmaceutical Sciences University of Geneva SwitzerlandMolecular Pharmacology Group School of Pharmaceutical Sciences University of Geneva SwitzerlandDepartment of Medical Oncology Cancer Center Amsterdam Amsterdam UMC Vrije Universiteit Amsterdam The NetherlandsDepartment of Medical Oncology Cancer Center Amsterdam Amsterdam UMC Vrije Universiteit Amsterdam The NetherlandsiGE3 Genomics Platform University of Geneva SwitzerlandTranslational Department of Digestive and Transplant Surgery Geneva University Hospitals and Faculty of Medicine SwitzerlandTranslational Department of Digestive and Transplant Surgery Geneva University Hospitals and Faculty of Medicine SwitzerlandDepartment of Medical Oncology Cancer Center Amsterdam Amsterdam UMC Vrije Universiteit Amsterdam The NetherlandsDepartment of Oncology University of Lausanne SwitzerlandDepartment of Oncology University of Lausanne SwitzerlandiGE3 Genomics Platform University of Geneva SwitzerlandDivision of Clinical Pathology Diagnostic Department University Hospitals of Geneva (HUG) SwitzerlandDepartment of Medical Oncology Cancer Center Amsterdam Amsterdam UMC Vrije Universiteit Amsterdam The NetherlandsDivision of Clinical Pharmacology and Toxicology Department of Anaesthesiology Intensive Care and Emergency Medicine Geneva University Hospitals Pharmacology SwitzerlandAngiogenesis Laboratory Department of Medical Oncology Cancer Center Amsterdam Amsterdam UMC‐location VUmc VU University Amsterdam The NetherlandsDivision of Clinical Pathology Diagnostic Department University Hospitals of Geneva (HUG) SwitzerlandTranslational Research Center in Oncohaematology Geneva SwitzerlandMolecular Pharmacology Group School of Pharmaceutical Sciences University of Geneva SwitzerlandThe current standard of care for colorectal cancer (CRC) is a combination of chemotherapeutics, often supplemented with targeted biological drugs. An urgent need exists for improved drug efficacy and minimized side effects, especially at late‐stage disease. We employed the phenotypically driven therapeutically guided multidrug optimization (TGMO) technology to identify optimized drug combinations (ODCs) in CRC. We identified low‐dose synergistic and selective ODCs for a panel of six human CRC cell lines also active in heterotypic 3D co‐culture models. Transcriptome sequencing and phosphoproteome analyses showed that the mechanisms of action of these ODCs converged toward MAP kinase signaling and cell cycle inhibition. Two cell‐specific ODCs were translated to in vivo mouse models. The ODCs reduced tumor growth by ~80%, outperforming standard chemotherapy (FOLFOX). No toxicity was observed for the ODCs, while significant side effects were induced in the group treated with FOLFOX therapy. Identified ODCs demonstrated significantly enhanced bioavailability of the individual components. Finally, ODCs were also active in primary cells from CRC patient tumor tissues. Taken together, we show that the TGMO technology efficiently identifies selective and potent low‐dose drug combinations, optimized regardless of tumor mutation status, outperforming conventional chemotherapy.https://doi.org/10.1002/1878-0261.12797colorectal carcinomacombination treatmentdrug–drug interactionsdrug–target interactionsphosphoproteomicssynergy |