研制靶向EGFR的高亲和力、低脂溶性小分子探针用于PET显像筛选NSCLC靶向治疗敏感个体

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are targeted drugs for non-small cell lung cancer (NSCLC), but they are only effective in patients with positive EGFR gene-sensitive mutations. Traditional EGFR gene mutation detection using pathological biopsy or liquid biopsy techniques. It can’t overcome the problem of tumor heterogeneity. PET imaging can detect EGFR mutation status in vivo, in real time and comprehensively, and provide accurate information on tumor size, shape and location. However, these agents currently have mang disadvantages such as high-lipophilicity, low- affinity and short half-life. In view of this, this project intends to development of a novel small molecule probe targeting EGFR with high-affinity, low-lipophilicity to screen sensitive individuals for NSCLC targeted therapy by PET imaging. At the first, using the clinical drug erlotinib as the mother to modify, screen, and labeled by 18F as a probe; At the second, through the biological evaluation of the probe and the PET imaging of model mouse, predicting the positive imaging models as the sensitive individuals; At the end, targeted therapy of tumor-bearing mice by EGFR-TKIs to verify prediction. In order to obtain a PET probe that can be non-invasively and accurately predict sensitive individuals for EGFR-TKIs, and can be widely used in clinical practice.

表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）作为非小细胞肺癌（NSCLC）靶向治疗一线药物，对EGFR基因突变患者疗效显著优于化疗。故明确EGFR基因突变以筛选靶向治疗敏感个体是提升疗效的关键。传统EGFR基因检测采用病理活检或液体活检技术，均无法克服肿瘤异质性问题。PET显像有望在体、实时、全面地对NSCLC患者进行EGFR突变检测，但目前此类探针存在脂溶性大、亲和力低、半衰期短等缺陷。鉴于此，本项目拟研制靶向EGFR的高亲和力、低脂溶性小分子探针用于PET显像筛选NSCLC靶向治疗敏感个体。主要包括：①以临床药物埃罗替尼为母体进行改性筛选，构建18F标记的PET探针；②通过探针生物学评价及荷瘤鼠PET显像，预测阳性显像模型为敏感个体；③EGFR-TKIs治疗模型鼠，并跟踪显像验证预测。以期获得一种能广泛用于临床的PET探针，可在体有效的预测EGFR-TKIs治疗敏感个体。

表皮生长因子受体（EGFR）与肿瘤细胞的增殖、血管生成、肿瘤侵袭、转移及细胞凋亡的抑制有关，是肿瘤靶向治疗的重要靶点。目前有多种靶向EGFR的小分子酪氨酸激酶抑制剂和抗体被批准用于非小细胞肺癌治疗，明确EGFR的表达及基因突变以筛选靶向治疗敏感个体是提升疗效的关键。传统EGFR基因检测采用病理活检或液体活检技术，均无法克服肿瘤异质性问题。PET显像有望在体、实时、全面地对NSCLC患者进行EGFR表达及突变检测，但目前此类探针存在脂溶性大、亲和力低、半衰期短等缺陷。本项目设计、合成、筛选了多个靶向EGFR的小分子PET探针，并进行了系列的体内外生物学评价及显像研究，以期开发新型PET探针以指导临床诊疗。项目具体开展了如下工作：一、开发了两个特异性靶向19外显子缺失EGFR的小分子PET探针，特别是6-O-[18F]FEE体内外评价及显像研究结果显示，能在EGFR19外显子缺失的肿瘤模型HCC827中特异性高摄取，具有筛选临床应用最广泛的第一代EGFR-TKIs治疗敏感患者的潜力，还可监测耐药情况并评估疗效，对EGFR19外显子缺失的患者实现精准诊疗；二、研制了两个靶向EGFR的小分子多肽类免疫PET探针（[18F]FP-Lys-GE11、[18F]AlF-NOTA-DGE11），能在体实时对EGFR表达情况进行可视化，肿瘤/肌肉比值较高可达10左右，背景脏器摄取除了肾脏均较低，具有指导靶向EGFR抗体免疫治疗的应用前景。本项目发表SCI论文5篇，申请专利5项，目前获授权专利3项，项目有两个探针分子具有进一步临床试验及应用的潜力，相关后续工作正在积极开展。