Predicting cetuximab accumulation in KRAS wild-type and KRAS mutant colorectal cancer using 64Cu-labeled cetuximab positron emission tomography
Predicting cetuximab accumulation in KRAS wild-type and KRAS mutant colorectal cancer using 64Cu-labeled cetuximab positron emission tomography
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DOI：
10.1111/j.1349-7006.2011.02166.x
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发表时间：
2012-03-01
期刊：
影响因子：
5.7
通讯作者：
Endo, Keigo
中科院分区：
文献类型：
--
作者：
Achmad, Arifudin;Hanaoka, Hirofumi;Endo, Keigo
表皮生长因子受体(EGFR)的过度表达在结直肠癌中十分常见。然而，西妥昔单抗作为一种EGFR靶向药物只对一小部分患者有效，目前除了V-Ki-ras2 Kirsten鼠肉瘤病毒癌基因同源突变(KRAS)之外，还没有单一的预测因素被确定。在本研究中，我们使用111In-DOTA-西妥昔单抗研究了西妥昔单抗在结直肠肿瘤和主要器官中的蓄积。我们还评价了正电子发射断层扫描(PET)对64铜-DOTA-西妥昔单抗的成像潜力。在注射放射性标记西妥昔单抗48h后，对不同EGFR表达水平和KRAS突变状态的结直肠癌移植瘤进行体内生物分布研究和PET成像。采用体外免疫印迹和酶联免疫吸附试验检测EGFR在大肠肿瘤组织中的表达水平。我们发现KRAS野生型肿瘤的111In-DOTA-西妥昔单抗蓄积量显著高于KRAS突变型肿瘤(P<；0.001)。根据KRAS突变情况，111In-DOTA-西妥昔单抗的肿瘤摄取率与EGFR表达水平呈正相关(KRAS野生型：r=0.988；KRAS突变型：r=0.829)；64CuDOTA-西妥昔单抗的肿瘤摄取量与EGFR表达水平呈正相关(KRAS野生型：r=0.838；KRAS突变型：r=0.927)。111In-DOTA-西妥昔单抗与64Cu-DOTA-西妥昔单抗的肿瘤摄取之间也存在显著的相关性(r=0.920)。~(64)Cu-DOTA-西妥昔单抗的PET成像可清晰显示肿瘤。这两种放射性标记西妥昔单抗都有效地显示了西妥昔单抗在大肠肿瘤中的蓄积，其EGFR表达水平和临床上常见的不同KRAS突变状态各不相同。因此，我们的研究结果表明，这种放射免疫成像技术可以作为西妥昔单抗治疗前西妥昔单抗在结直肠癌患者体内蓄积预测的一种临床工具。(《癌症科学》2012年版，第103期：600605页)
Overexpression of epidermal growth factor receptor (EGFR) is common in colorectal cancer. However, cetuximab as an EGFR-targeting drug is useful only for a subset of patients and currently no single predictor other than V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status has been established. In the present study, we investigated cetuximab accumulation in colorectal tumors and major organs using 111In-DOTA-cetuximab. We also evaluated the potential of positron emission tomography (PET) imaging of 64Cu-DOTA-cetuximab. Colorectal tumor xenografts with a different EGFR expression level and KRAS mutation status were subjected to in vivo biodistribution study and PET imaging at 48 h post-injection of radiolabeled cetuximab. The EGFR expression levels on colorectal tumors were determined by ex vivo immunoblotting and ELISA. We found that KRAS wild-type tumors had significantly higher 111In-DOTA-cetuximab accumulation than KRAS mutant tumors (P < 0.001). Based on KRAS mutation status, a strong correlation was found between 111In-DOTA-cetuximab tumor uptake and EGFR expression level (KRAS wild type: r = 0.988; KRAS mutant: r = 0.829), and between 64Cu-DOTA-cetuximab tumor uptake with EGFR expression level (KRAS wild type: r = 0.838; KRAS mutant: r = 0.927). Significant correlation was also found between tumor uptake of 111In-DOTA-cetuximab and 64Cu-DOTA-cetuximab (r = 0.920). PET imaging with 64Cu-DOTA-cetuximab allowed clear visualization of tumors. Both radiolabeled cetuximab had effectively visualized cetuximab accumulation in colorectal tumors with a wide variety of EGFR expression levels and different KRAS mutation status as commonly encountered in the clinical setting. Our findings suggest that this radioimmunoimaging therefore can be clinically translated as an in vivo tool to predict cetuximab accumulation in colorectal cancer patients prior to cetuximab therapy. (Cancer Sci 2012; 103: 600605)