UNIGE document Scientific Article
previous document  unige:142854  next document
add to browser collection
Title

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

Authors
Beijnum, Judy R.
Weiss, Andrea
Piersma, Sander R.
show hidden authors show all authors [1 - 23]
Published in Molecular Oncology. 2020
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 carcinomaCombinationTreatmentDrug–drug interactionsDrug–Target interactionsPhosphoproteomicsSynergy
Identifiers
PMID: 33021054
Full text
Structures
Research groups Pharmacologie moléculaire
Métastases du foie (657)
Immunothérapie des cancers (42)
Lymphomes MALT et réplication virale (807)
Transplantation et hépatologie (905)
Groupe Desmeules Jules (pharmacologie/toxicologie) (567)
Pharmaco-omiques et médecine de précision (1003)
Project
H2020: OPTIM
Citation
(ISO format)
ZOETEMELK, Marloes et al. Optimized low‐dose combinatorial drug treatment boosts selectivity and efficacy of colorectal carcinoma treatment. In: Molecular Oncology, 2020. doi: 10.1002/1878-0261.12797 https://archive-ouverte.unige.ch/unige:142854

205 hits

59 downloads

Update

Deposited on : 2020-10-12

Export document
Format :
Citation style :