11C-PD153035 PET/CT筛选非小细胞肺癌EGFR突变和监测EGFR-TKIs疗效的研究

The epidermal growth factor receptor (EGFR) has been extensively investigated as a target of antineoplastic therapy in advanced-stage non-small cell lung cancer (NSCLC). Sequencing of the EGFR gene revealed that most tumors that respond to EGFR kinase inhibitors harbor activating mutations in the EGFR kinase domain. Activating EGFR mutations, including either in-frame deletions in exon 19 or point mutation in exons 20 and 21 play an improtant role in determining responsiveness or resistance to small molecule tyrosine kinase inhibitors (TKIs). Detecting EGFR mutations using tumor tissues obtained via a biopsy or surgical resection is now routinely used to diagnosed NSCLC. In particular, noninvasive tests allow the frequent monitoring of disease progression in patients with the exon 20 mutation. Because a biopsy is an invasive procedure, it is desirable to replace it with a noninvasive procedure. The complexity and limitations of invasive methods of analysis of EGFR mutations prompted the development of novel radiolabeled agents for noninvasive PET imaging, which may help in identificantion of NSCLC paitnets who may benefit from EGFR kinase inhibitors. 11C-labeled 4-N-(3-bromoanilino)-6,7-dimethoxyquinazoline (11C-PD153035), a positron-emitting analog of the EGFR-TKI PD153035, was developed as a noninvasive imaging biomarker for tumor EGFR status using PET. We previously demonstrated preclincially that 11C-PD153035 tumor uptake correlates with EGFR expression and characterized its biodistribution in health human volunteer as well as demonstrated tumor uptake in patients with NSCLC. We postulate that 11C-PD153035 PET/CT has the potential to serve as an imaging biomaker for predicting which patients will benefit most from EGFR-TKI treatment. Therefore, the aim of this study is to detect whether 11C-PD153035 PET/CT is selective of the EGFR mutation in tumor tissue from surgical NSCLC patients, and to detect whether 11C-PD153035 PET/CT is selective of the EGFR mutation in tumor tissue by biopsy from advaced-stage NSCLC patients who will be treated with EGFR-TKIs or acquired resistance to them. Then, we will see to determine whether 11C-PD153035 PET/CT correlated with outcomes in patients treated with EGFR-TKIs for advanced chemotherapy-refractory NSCLC.

表皮生长因子受体（EGFR）突变被认为是酪氨酸激酶抑制剂（TKIs）治疗非小细胞肺癌（NSCLC）有效的重要预测指标。目前检测突变的手段多为有创性，不易重复获取,不能全面评价肿瘤组织EGFR状态。分子影像技术是无创性动态检测EGFR的理想方法。我们已成功合成与TKIs相似分子结构的新型PET示踪剂11C-PD153035,证实它能对NSCLC患者的肿瘤病灶显像,具有筛选EGFR状态的潜在可能。在此基础上，本项目拟以DNA测序法和SARMS法检测肿瘤组织EGFR突变作为金标准,验证动物和NSCLC手术患者肿瘤病灶PD153035分子影像参数与肿瘤组织EGFR突变的相关性；验证EGFR-TKIs治疗前、治疗进展或耐药时肿瘤病灶分子影像参数与肿瘤组织、外周血清EGFR突变的相关性并研究治疗前和治疗过程中病灶分子影像参数与疾病变化的关系，从而为EGFR-TKIs患者选择与疗效评价提供新型有效手段。

表皮生长因子受体（EGFR）突变被认为是酪氨酸激酶抑制剂（TKIs）治疗非小细胞肺癌（NSCLC）有效的重要预测指标。目前检测突变的手段多为有创性，不易重复获取,不能全面评价肿瘤组织EGFR状态。分子影像技术是无创性动态检测EGFR的理想方法。我们已成功合成与TKIs相似分子结构的新型PET示踪剂11C-PD153035,证实它能对NSCLC患者的肿瘤病灶显像,具有筛选EGFR状态的潜在可能。在此基础上，我们制作荷瘤鼠模型，利用小动物PET，获得11C-PD153035 PET分子影像的相关参数（SUV、T/N）；采用DNA测序法、SARMS法检测肿瘤组织EGFR突变状态；分析EGFR分子影像相关参数与肿瘤组织EGFR突变的相关性。进而对经病理证实的NSCLC腺癌患者，利用11C-PD153035 PET/CT，获得术前原发病灶和区域转移淋巴结EGFR分子影像的相关参数（SUV、T/N）；采用SARMS法检测术前外周血清EGFR突变状态，采用DNA测序法和SARMS法检测术后肿瘤组织的EGFR突变状态；分析EGFR分子影像相关参数与外周血清、肿瘤组织EGFR突变的相关性。研究结果发现11C-PD153035在荷瘤鼠体内快速分布与代谢，在4分钟内心脏的放射活性达高峰，然后快速下降；而肝脏、胃肠道的放射活性分别于10-20分钟、30分钟时逐渐升至高峰，并在扫描过程中保持较高的浓度；11C-PD153035注射后2分钟时肾脏可见放射活性聚集，并逐渐增强，4分钟后膀胱内可见放射活性。而在脑组织、肺、骨及软组织放射活性分布相对较低，脑组织内放射活性在2分钟时可见，4分钟时达高峰后逐渐下降。肺内的放射活性在8分钟时达高峰，然后逐渐下降。生殖腺，如两侧睾丸内也有较高的放射活性分布。在体研究初步发现患者的胸部PET图像及PET/CT融合图像结果均显示，11C-PD153035在胸部各器官及组织中均表现为低摄取，胸部本底低，适合行NSCLC的肿瘤显像。并且PET/CT高摄取与EGFR突变有一定相关性，从而为EGFR-TKIs患者选择与疗效评价提供新型有效手段。

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