Platform combining statistical modeling and patient-derived organoids to facilitate personalized treatment of colorectal carcinoma
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George M Ramzy1,2,3, Maxim Norkin4, Thibaud Koessler5
1Molecular Pharmacology Group, School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, CMU, 1211, Geneva 4, Switzerland.
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.
Insights
Personalized colorectal cancer (CRC) treatment is enhanced by combining organoid drug testing with mathematical modeling. Therapeutically Guided Multidrug Optimization (TGMO) identifies synergistic drug combinations outperforming standard chemotherapy.
Area of Science:
- Oncology
- Translational Medicine
- Pharmacology
Background:
- Colorectal cancer (CRC) treatment requires personalized strategies.
- Ex vivo organoid efficacy testing and mathematical modeling offer a novel approach.
Purpose of the Study:
- To develop and validate a personalized treatment design for CRC patients.
- To identify optimized drug combinations (ODCs) using Therapeutically Guided Multidrug Optimization (TGMO).
Main Methods:
- Utilized TGMO, a validated phenotypic approach, to identify low-dose synergistic ODCs.
- Employed second order linear regression and adaptive lasso for data analysis.
- Validated ODCs on patient-derived organoids (PDOs) from primary and metastatic CRC cases.
Main Results:
- ODCs demonstrated significant inhibition of cell viability (up to 88%) in stage IV CRC PDOs, outperforming FOLFOXIRI.
- Patient-specific TGMO-based ODCs showed superior efficacy compared to standard chemotherapy.
- Molecular characterization of CRC using whole-exome sequencing and RNAseq informed the study.
Conclusions:
- The proposed approach enables rapid optimization of patient-tailored synergistic multi-drug combinations.
- This method offers a clinically relevant timeframe for personalized CRC treatment design.
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