难治性甲状腺癌的靶向治疗.ppt

47%的病人需要减少剂量 不良事件：手足红斑、疹，骨肌疼痛，瘙痒症，高血压，腹泻，疲劳，体重减轻，口腔炎，秃发，腹胀，情绪改变等 2008年NCCN同意sorafenib临床进展或有症状的碘抵抗的乳头状癌的治疗 阿西替尼Axitinib（AG-013736) 口服多靶点酪氨酸激酶抑制剂 同时具有选择性抑制VEGFRs Axitinib Rixe et al 2007 renal cell carcinoma Cohen et al 2008 advanced thyroid cancer multicenter phase 2 study 60 case 30%PR 38% SD 4 months median PFS 18 months PTC 27% PR 40%SD Motesanib(AMG 706) Motesanib is a multi-targeted tyrosine kinase inhibitor that targets the VEGFRs, PDGFR, and c-kit multicenter international phase II trial of motesanib 93 patients with radioiodine-resistant, progressive DTC orally at a dose of 125 mg orally daily (Sherman et al. 2008) Schlumberger et al. 2007 multicenter international open label phase II trial of motesanib in MTC, patients with locally advanced or metastatic, progressive or symptomatic MTC 91 patients, 2% PRs ，47% SDs 6 months duration. median PFS was 12 months Objective response 14% PRs, 67% SD and a 35% SD 6 months duration median PFS was 10 months 81% had decreased serum Tg concentrations during treatment as compared with baseline Sunitinib (SU 011248) Sunitinib is approved through the FDA for patients with metastatic renal cell carcinoma or imitanib refractory gastrointestinal stromal tumors. Cohen et al. 2008a phase II study of sunitinib 37 patients with iodine-refractory progressive DTC PR in 13%, SD in 68%, progressive disease in 10% Goulart et al. 2008,Ravaud et al. 2008 Results are awaited for other ongoing phase II trials of sunitinib in patients with iodine-refractory DTC and metastatic MTC 细胞信号传导通路上的靶点治疗 吉非替尼Gefitinib（Irassa,ZD1839):是一种选择性表皮生长因子受体(EGFR)酪氨酸受体激酶抑制剂，具有高度选择性，通过阻止EGF刺激的EGFR自磷酸化和EGFR介导的下游信号转到而发挥作用。 该酶通常表达于上皮来源的实体瘤，对于EGFR酪氨酸激酶活性的抑制可妨碍肿瘤的生长、转移和血管生成，并增加肿瘤细胞的凋亡，阻断EGF诱导的体外肿瘤的生长，临床研究显示EGFR在正常及恶性甲状腺组织中均有高表达，在分化型甲状腺癌中常提示预后不佳 体外实验已显示吉非替尼的抗甲状腺癌作用，在ATC细胞系中可清晰观察到对EGFR转到的生长刺激抑制作用 吉非替尼二期临床试验结果 27例放射性碘抵抗、局部进展以及远处转移的患者口服吉非替尼250mg/d,12月后评估 32%肿瘤体积缩减，12%保持肿瘤无进展,其中5例患者甲状腺球蛋白降至基准水平的10%以上并保持3月以上 Pennell N