In identifying biomarkers for anticancer drugs, the lack of objectivity in selecting candidate factors makes interpretation difficult. We performed preclinical analysis and a translational validation study to identify candidate biomarkers for regorafenib efficacy in metastatic colorectal cancer (mCRC). Using in silico COMPARE analysis with a human cancer cell line panel, JFCR39, we selected candidate biomarkers whose expression correlates with regorafenib sensitivity. We validated predictive values in mCRC patients receiving regorafenib (discovery,n= 53) and FTD/TPI (control,n= 16). Blood samples were obtained at baseline (BL), before the second cycle (2nd), and at progressive disease (PD), and biomarker levels were measured using ELISA. Our analysis showed that high matrix metalloproteinase (MMP)-14 expression was associated with a high sensitivity to regorafenib. In the discovery cohort, high MMP-14 levels at BL and PD were correlated with tumor shrinkage and longer progression-free survival (PFS). A subsequent analysis of other related factors further indicated that the patients with decreased MMP-9 levels at the 2nd had higher disease control rates, tumor shrinkage, longer PFS, and overall survival than those with increased changes. These findings were not observed in the control cohort. Our study suggests MMP-14 and MMP-9 may serve as prognostic markers for regorafenib and provide insights into novel combination therapies with anti-MMP-9 agents or FTD/TPI.
在识别抗癌药物生物标志物的过程中，候选因子选择缺乏客观性导致结果解读困难。本研究通过临床前分析与转化验证实验，探索瑞戈非尼治疗转移性结直肠癌（mCRC）疗效的潜在生物标志物。采用人癌细胞系JFCR39进行计算机COMPARE分析，筛选出与瑞戈非尼敏感性相关的候选生物标志物。随后在接受瑞戈非尼治疗（探索队列，n=53）和FTD/TPI治疗（对照队列，n=16）的mCRC患者中进行预测价值验证。分别在基线期（BL）、第二周期前（2nd）和疾病进展期（PD）采集血液样本，通过ELISA法检测生物标志物水平。分析显示，基质金属蛋白酶（MMP）-14高表达与瑞戈非尼高敏感性相关。在探索队列中，BL期和PD期高MMP-14水平与肿瘤缩小及较长无进展生存期（PFS）相关。进一步分析发现，与水平升高的患者相比，2nd期MMP-9水平下降的患者具有更高的疾病控制率、更显著的肿瘤缩小、更长的PFS和总生存期。这些现象在对照队列中均未观察到。本研究提示MMP-14和MMP-9可作为瑞戈非尼疗效的预后标志物，并为抗MMP-9药物或FTD/TPI的联合治疗方案提供新思路。
肿瘤(癌症)患者之家