Studies on effective molecular targeted therapy for head and neck cancer

本研究所建立的16例头颈部鳞状细胞癌均表达EGFR蛋白和mRNA。16株HNSCC细胞均检测到EGFR基因第20外显子的静止性异质性突变，但未发现与EGFR抑制剂敏感性相关的第19外显子或第20外显子突变。20外显子突变的细胞对EGFR抑制剂之一的吉非替尼的敏感性高于未突变的细胞(野生型)。在16个细胞株中，有6个细胞株联合应用吉非替尼和赫赛汀的生长抑制率高于单独使用吉非替尼。联合治疗的抗肿瘤机制被认为是阻断了EGFR和HER之间的异二聚化。2.贝伐单抗是EGFR和血管内皮生长因子的双重抑制剂，在人HNSCC裸鼠移植模型中显示出很强的抗肿瘤作用。尤其是贝伐单抗和紫杉醇治疗的肿瘤完全消失。从抗肿瘤机制上证实了其诱导细胞凋亡和抑制血管生成的作用。

All the 16 head and neck squamous cell carcinoma (HNSCC) established in our institute expressed EGFR protein and mRNA. Silent heterogous mutation on exon 20 of EGFR gene was detected in all the 16 cell lines, however mutation on exon 19 or exon 20 associated with sensitivity to EGFR inhibitor was not observed in these 16 HNSCC lines.The cell lines with mutation on exon 20 was more sensitive to gefitinib, one of EGFR inhibitors, than the cell lines without mutation (wild type).The exprssions of HER2 protein and mRNA were observed in these 16 cell lines hoeever the growth of these cell lines was not inhibited by the treatment of herceptin, monoclonal antibody against HER2, alone. In 6 of 16 cell lines, the combined treatment of gefitinib and herceptin showed a higher growth inhibition than the treatment of gefitinib alone. The anti-tumor mechanism of the combined treatment is thought to be a blockage of heterodimarization between EGFR and HER.2.On the other hand bevacizumab which is a dual inhibitor of EGFR and VEGF, showed a strong anti-tumor effect in a model using nude mice transplanted with a human HNSCC line. Especially, the tumor treated with bevacizumab and paclitaxel completely disappeared. The induction of apoptosis and inhibition of angiogenesis were confirmed in terms of the anti-tumor mechanisms.