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  3. Optimized low-dose combinatorial drug treatment boosts selectivity and efficacy of colorectal carcinoma treatment

Optimized low-dose combinatorial drug treatment boosts selectivity and efficacy of colorectal carcinoma treatment

  • Mol Oncol. 2020 Nov;14(11):2894-2919. doi: 10.1002/1878-0261.12797.
Marloes Zoetemelk 1 2 3,  George M Ramzy 1 2 3,  Magdalena Rausch 1 2 3,  Thibaud Koessler 4,  Judy R van Beijnum 5,  Andrea Weiss 1 2,  Valentin Mieville 1 2,  Sander R Piersma 6 7,  Richard R de Haas 6 7,  Céline Delucinge-Vivier 8,  Axel Andres 9 10,  Christian Toso 9 10,  Alexander A Henneman 6 7,  Simone Ragusa 11 12,  Tatiana V Petrova 11 12,  Mylène Docquier 8 13,  Thomas A McKee 14,  Connie R Jimenez 6 7,  Youssef Daali 15,  Arjan W Griffioen 5,  Laura Rubbia-Brandt 14,  Pierre-Yves Dietrich 3 4,  Patrycja Nowak-Sliwinska 1 2 3
Affiliations

Affiliations

  • 1 Molecular Pharmacology Group, School of Pharmaceutical Sciences, University of Geneva, Switzerland.
  • 2 Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Switzerland.
  • 3 Translational Research Center in Oncohaematology, Geneva, Switzerland.
  • 4 Department of Oncology, Geneva University Hospitals and Faculty of Medicine, Switzerland.
  • 5 Angiogenesis Laboratory, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC-location VUmc, VU University Amsterdam, The Netherlands.
  • 6 Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, The Netherlands.
  • 7 OncoProteomics Laboratory, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, The Netherlands.
  • 8 iGE3 Genomics Platform, University of Geneva, Switzerland.
  • 9 Translational Department of Digestive and Transplant Surgery, Geneva University Hospitals and Faculty of Medicine, Switzerland.
  • 10 Hepato-Pancreato-Biliary Centre, Geneva University Hospitals and Faculty of Medicine, Switzerland.
  • 11 Department of Oncology, University of Lausanne, Switzerland.
  • 12 Ludwig Institute for Cancer Research Lausanne, Switzerland.
  • 13 Department of Genetics & Evolution, University of Geneva, Switzerland.
  • 14 Division of Clinical Pathology, Diagnostic Department, University Hospitals of Geneva (HUG), Switzerland.
  • 15 Division of Clinical Pharmacology and Toxicology, Department of Anaesthesiology, Intensive Care and Emergency Medicine, Geneva University Hospitals, Pharmacology, Switzerland.
PMID: 33021054 DOI: 10.1002/1878-0261.12797
Abstract

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.

Keywords

colorectal carcinoma; combination treatment; drug-drug interactions; drug-target interactions; phosphoproteomics; synergy.

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