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  4. Platform combining statistical modeling and patient-derived organoids to facilitate personalized treatment of colorectal carcinoma
 
research article

Platform combining statistical modeling and patient-derived organoids to facilitate personalized treatment of colorectal carcinoma

Ramzy, George M.
•
Norkin, Maxim  
•
Koessler, Thibaud
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April 3, 2023
Journal Of Experimental & Clinical Cancer Research

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.

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Type
research article
DOI
10.1186/s13046-023-02650-z
Web of Science ID

WOS:000964171100001

Author(s)
Ramzy, George M.
Norkin, Maxim  
Koessler, Thibaud
Voirol, Lionel
Tihy, Mathieu
Hany, Dina
McKee, Thomas
Ris, Frederic
Buchs, Nicolas
Docquier, Mylene
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Date Issued

2023-04-03

Publisher

BMC

Published in
Journal Of Experimental & Clinical Cancer Research
Volume

42

Issue

1

Start page

79

Subjects

Oncology

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Oncology

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drug-drug interaction

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drug resistance

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multidrug combination

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organoid

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phenotypic screen

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synergy

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targeted rnaseq

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microsatellite instability

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receptor inhibitor

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drug-combinations

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phase-i

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cancer

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pharmacokinetics

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tumors

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regorafenib

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mutation

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bez235

Editorial or Peer reviewed

REVIEWED

Written at

EPFL

Available on Infoscience
May 8, 2023
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/197485
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