Suenaga Mitsukuni, Mashima Tetsuo, Kawata Naomi, Dan Shingo, Seimiya Hiroyuki, Yamaguchi Kensei
Gastroenterology Center, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
Department of Clinical Oncology, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Cancers (Basel). 2024 Aug 15;16(16):2855. doi: 10.3390/cancers16162855.
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, = 53) and FTD/TPI (control, = 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.
在确定抗癌药物的生物标志物时，选择候选因素缺乏客观性使得解读变得困难。我们进行了临床前分析和转化验证研究，以确定瑞戈非尼治疗转移性结直肠癌（mCRC）疗效的候选生物标志物。通过对人类癌细胞系面板JFCR39进行计算机比较分析，我们选择了表达与瑞戈非尼敏感性相关的候选生物标志物。我们在接受瑞戈非尼治疗的mCRC患者（发现队列，n = 53）和接受FTD/TPI治疗的患者（对照队列，n = 16）中验证了预测价值。在基线（BL）、第二个周期前（第2周期）和疾病进展（PD）时采集血样，并使用酶联免疫吸附测定法（ELISA）测量生物标志物水平。我们的分析表明，高基质金属蛋白酶（MMP）-14表达与对瑞戈非尼的高敏感性相关。在发现队列中，BL和PD时的高MMP-14水平与肿瘤缩小和更长的无进展生存期（PFS）相关。对其他相关因素的后续分析进一步表明，第2周期时MMP-9水平降低的患者比MMP-9水平升高的患者具有更高的疾病控制率、肿瘤缩小、更长的PFS和总生存期。在对照队列中未观察到这些结果。我们的研究表明，MMP-14和MMP-9可能作为瑞戈非尼的预后标志物，并为与抗MMP-9药物或FTD/TPI的新型联合治疗提供见解。
