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

George Ramzy, Maxim Norkin, Thibaud Koessler, Lionel Voirol, Mathieu Tihy, Dina Hany, Thomas Mckee, Frédéric Ris, Nicolas Buchs, Mylène Docquier, Christian Toso, Laura Rubbia-Brandt, Gaetan Bakalli (), Stéphane Guerrier, Joerg Huelsken and Patrycja Nowak-Sliwinska
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George Ramzy: UNIGE - Université de Genève = University of Geneva
Maxim Norkin: EPFL - Ecole Polytechnique Fédérale de Lausanne
Thibaud Koessler: HUG - Hôpitaux Universitaires de Genève = University Hospital of Geneva [Genève]
Lionel Voirol: UNIGE - Université de Genève = University of Geneva
Mathieu Tihy: HUG - Hôpitaux Universitaires de Genève = University Hospital of Geneva [Genève]
Dina Hany: UNIGE - Université de Genève = University of Geneva
Thomas Mckee: HUG - Hôpitaux Universitaires de Genève = University Hospital of Geneva [Genève]
Frédéric Ris: HUG - Hôpitaux Universitaires de Genève = University Hospital of Geneva [Genève]
Nicolas Buchs: HUG - Hôpitaux Universitaires de Genève = University Hospital of Geneva [Genève]
Mylène Docquier: UNIGE - Université de Genève = University of Geneva
Christian Toso: HUG - Hôpitaux Universitaires de Genève = University Hospital of Geneva [Genève]
Laura Rubbia-Brandt: HUG - Hôpitaux Universitaires de Genève = University Hospital of Geneva [Genève]
Gaetan Bakalli: EM - EMLyon Business School
Stéphane Guerrier: UNIGE - Université de Genève = University of Geneva
Joerg Huelsken: EPFL - Ecole Polytechnique Fédérale de Lausanne
Patrycja Nowak-Sliwinska: UNIGE - Université de Genève = University of Geneva

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Abstract: 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.

Date: 2023-04-03
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Published in Journal of experimental & clinical cancer research, 2023, 42 (1), ⟨10.1186/s13046-023-02650-z⟩

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Persistent link: https://EconPapers.repec.org/RePEc:hal:journl:hal-05677531

DOI: 10.1186/s13046-023-02650-z

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