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

Details

Serval ID
serval:BIB_6B1C1DF10DF7
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Optimized low-dose combinatorial drug treatment boosts selectivity and efficacy of colorectal carcinoma treatment.
Journal
Molecular oncology
Author(s)
Zoetemelk M., Ramzy G.M., Rausch M., Koessler T., van Beijnum J.R., Weiss A., Mieville V., Piersma S.R., de Haas R.R., Delucinge-Vivier C., Andres A., Toso C., Henneman A.A., Ragusa S., Petrova T.V., Docquier M., McKee T.A., Jimenez C.R., Daali Y., Griffioen A.W., Rubbia-Brandt L., Dietrich P.Y., Nowak-Sliwinska P.
ISSN
1878-0261 (Electronic)
ISSN-L
1574-7891
Publication state
In Press
Peer-reviewed
Oui
Language
english
Notes
Publication types: Journal Article
Publication Status: aheadofprint
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
Pubmed
Web of science
Open Access
Yes
Create date
09/10/2020 11:40
Last modification date
04/11/2020 6:23
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