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.
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.
摘要：
背景：我们提出了一种针对结直肠癌（CRC）患者设计个性化治疗的新方法，通过将体外类器官功效测试与结果的数学建模相结合。
方法：经过验证的表型方法称为治疗指导多药优化（TGMO），用于在对一线CRC化疗（FOLFOXIRI）敏感或耐药的3D人类CRC细胞模型中鉴定四种低剂量协同优化药物组合（ODC）。我们的发现是使用二阶线性回归和自适应套索获得的。
结果：所有ODC的活性均在原发性或转移性CRC患者来源的类器官（PDO）上得到验证。使用全外显子组测序和RNAseq对CRC材料进行分子表征。在鉴别为CMS4/CRIS-A的肝转移（IV期）患者的PDO中，我们的ODC由雷戈拉非尼[1mM]组成，vemurafenib[11mM]，palbociclib[1mM]和拉帕替尼[0.5mM]抑制细胞活力达88%，显着优于临床剂量的FOLFOXIRI。此外，我们确定了基于患者特异性TGMO的ODC，其疗效优于当前化疗标准的治疗效果，FolfOXIRI.
结论：我们的方法允许在临床相关的时间范围内优化患者定制的协同多药组合。
方法：经过验证的表型方法称为治疗指导多药优化（TGMO），用于在对一线CRC化疗（FOLFOXIRI）敏感或耐药的3D人类CRC细胞模型中鉴定四种低剂量协同优化药物组合（ODC）。我们的发现是使用二阶线性回归和自适应套索获得的。
结果：所有ODC的活性均在原发性或转移性CRC患者来源的类器官（PDO）上得到验证。使用全外显子组测序和RNAseq对CRC材料进行分子表征。在鉴别为CMS4/CRIS-A的肝转移（IV期）患者的PDO中，我们的ODC由雷戈拉非尼[1mM]组成，vemurafenib[11mM]，palbociclib[1mM]和拉帕替尼[0.5mM]抑制细胞活力达88%，显着优于临床剂量的FOLFOXIRI。此外，我们确定了基于患者特异性TGMO的ODC，其疗效优于当前化疗标准的治疗效果，FolfOXIRI.
结论：我们的方法允许在临床相关的时间范围内优化患者定制的协同多药组合。
