难治性甲状腺癌的靶向治疗课件.pptx

1、nThyroid cancer is the most common malignancy of the endocrine systemn5-year disease-specific survival of patients with DTC with distant metastases is 50%(Shaha et al.1997,Hundahl et al.1998).nLike DTC,patients with metastatic disease do poorly,with a 5 year survival of 50%(Hundahl et al.1998).nmedi

2、an survival of this group of patients is 1 year.Sunitinib(SU 011248)索拉非尼是本类化合物中第一个进入临床试验，可在抑制Raf活性的剂量下，显著抑制肿瘤细胞增殖；索拉非尼是本类化合物中第一个进入临床试验，可在抑制Raf活性的剂量下，显著抑制肿瘤细胞增殖；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。索拉非尼是本类化合物中第一个进入临床试验，可在抑制Raf活性的剂量下

3、，显著抑制肿瘤细胞增殖；median survival of this group of patients is 6月 其中23例患者血浆肿瘤标记物降钙素至少下降50%并保持6周以上这条途径的激活将导致肿瘤的发生。近十年来，新的分子靶向药物不断涌现，已有的分子靶向药物也不断增加新的适应症。抗血管生成化合物CA4PKloos R,Ringel M,Knopp M,et al.组蛋白的乙酰化状态可以影响基因的表达，当组蛋白处于乙酰化状态时，由组蛋白与DNA双链构成的核小体结构变得更为开放，有利于各种转录因子与DNA的结合，启动基因的表达。其他研究中的甲状腺癌的靶向治疗药物1997,Hundahl

4、et al.nMotesanib is a multi-targeted tyrosine kinase inhibitornthat targets the VEGFRs,PDGFR,and c-kitnmulticenter 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.2007nmulti

5、center 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 responsen14%PRs,67%SD and a 35%SD 6nmonths durationnmedian PFS was 10 monthsn81

6、%had decreased serum Tgnconcentrations during treatment as compared with baselineSunitinib(SU 011248)Sunitinib is approved through the FDA for patients with metastatic renal cell carcinoma or imitanib refractory gastrointestinal stromal tumors.Cohen et al.2008anphase II study of sunitinib 37 patient

7、s with iodine-refractory progressive DTCn PR in 13%,SD in 68%,progressive disease in 10%nGoulart 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 MTCGefitinib53%的患者病情稳定长达14-89周.组蛋白的乙酰化状态可以影响基因的表达，当组蛋

8、白处于乙酰化状态时，由组蛋白与DNA双链构成的核小体结构变得更为开放，有利于各种转录因子与DNA的结合，启动基因的表达。这条途径的激活将导致肿瘤的发生。因此HDACi已成为一类新型的抗肿瘤制剂。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选择性靶向参与肿瘤扩散和生长的关键细胞信号传导途径，包括血管内皮生长因子和表皮生长因子受体信号。当组蛋白处于低乙酰化状态时，可出现转录抑制，并介导肿瘤的发生。PR i

9、n 13%,SD in 68%,progressive disease in 10%选择性靶向参与肿瘤扩散和生长的关键细胞信号传导途径，包括血管内皮生长因子和表皮生长因子受体信号。该研究接纳了30例不摄碘的甲状腺癌转移灶患者,进行了长达16周以上的口服治疗，400mg，2次/日。索拉非尼是本类化合物中第一个进入临床试验，可在抑制Raf活性的剂量下，显著抑制肿瘤细胞增殖；伊马替尼和达沙替尼治疗白血病；热休克蛋白分五类:HSP100、HSP90、HSP70、HSP60、小分子热休克蛋白（small Heat Shock Proteins).抑制驱动某些肿瘤生长和存活的RET激酶RET基因5端的跨膜

10、区和胞内酪氨酸激酶区可与不同异源基因重排形成RET/PTC基因，该类重排使RET基因启动子改变，从而激活该基因multicenter international phase II trial of motesanib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，情绪改变等这类药物单用大多有一定疗效，能明显提高化疗或放疗的疗效，已经有多种该类药物进入NCCN所制定的常见肿瘤治疗规范。2例（10%）完全缓解In preclinical studies,17-AAG was found to reduce RET/PTC1 proteinlevels,i

11、nduce cell death and increase the uptake of radioactive iodine into thyroid cancer cellsmulticenter international phase II trial of motesanib吉非替尼二期临床试验结果Kloos R,Ringel M,Knopp M,et al.Rixe et al 2007 renal cell carcinoma大约44%的甲状腺乳头状癌和约24%的甲状腺未分化癌会发生BRAF基因突变。索拉非尼是本类化合物中第一个进入临床试验，可在抑制Raf活性的剂量下，显著抑制肿瘤细

12、胞增殖；Bodei L,Handkiewicz-Junak D,Grana C,et al.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。目前SAHA已经在美国进入2期临床试验。Another phase II clinical trial evaluated efficacy of vandetanib in patients with hereditary MTC(Haddad et al.吉非替尼二期临床试验结果选择性COX

13、-2抑制剂塞来昔布治疗晚期分化性甲状腺癌未取得满意疗效Kloos R,Ringel M,Knopp M,et al.伊马替尼和达沙替尼治疗白血病；索拉非尼(商品名:多吉美)为德国拜耳先灵公司生产的一种口服多激酶抑制剂,可抑制肿瘤的细胞增殖和血管生成.羟胺类口服组蛋白去乙酰酶抑制剂SAHA治疗晚期甲状腺癌均取得一定疗效is ongoing.a phase II trial was conducted in 18 patients with metastatic ATC,good performance status,and noRET 基因定位于10号染色体，编码一种酪氨酸激酶受体超家族的跨膜蛋

14、白Pennell NA,Daniels GH,Haddad RI,at al.12例（57%）病情稳定平均无进展生存时间长达79周.nAnother phase II clinical trial evaluated efficacy of vandetanib in patients with hereditary MTC(Haddad et al.2008)n19 patients,2(10%)PRs and 6(42%)SD 6 monthsninternational phase III trial of vandetanib in sporadic and hereditary MT

15、C was recently completed and the results are eagerly awaited.XL-184nXL-184 is an oral multi-kinase inhibitor targeting RET,MET and VEGFR2.In a phase I clinical trial of XL-184,14 patients with MTC were enrolled(Salgia et al.2008).nThree PRs were noted among tennevaluable MTC patients,5696%reductions

16、 innserum calcitonin and 580%reductions in serum CEA were noted in all ten evaluable MTC patientsna phase II trial was conducted in 18 patients with metastatic ATC,good performance status,and no prior therapy for disseminated disease(Cooney et al.2006).Six patients had SDs while rest of the patients

17、 progressed.Median PFS was 1.8 months 28%of patients progression free 3 months.Median survival was 5 months.phase III study of paclitaxel and carboplatin with or without combretastatin is ongoing.17-AAGn17-AAG is a heat shock protein(Hsp)90 inhibitor thathas been identified as a potential therapeuti

18、c agent in thyroid cancer.Hsp 90 specifically has been found to be important to the signaling kinases Akt and RAF as well as formation of the PTC1 protein,which is the most common RET/PTC chimeric oncoprotein seen in PTC(Smida et al.1999).In preclinical studies,17-AAG was found to reduce RET/PTC1 pr

19、oteinlevels,induce cell death and increase the uptake of radioactive iodine into thyroid cancer cellsMotesanib AMG70632%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月以上尼妥珠单抗治疗恶性神经胶质瘤；伊马替尼治疗胃肠间质瘤。组蛋白的乙酰化状态可以影响基因的表达，当组蛋白处于乙酰化状态时，由组蛋白与DNA双链构成的核小体结构变得更为开放，有利于各种转录因子与DNA的结合，启动基因的表达。该酶通常表达于上皮来源的实体瘤，对于EGFR

20、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Kloos R,Ringel M,Knopp M,et al.RAF丝/苏氨酸激酶位于有丝分裂原活化蛋白激酶/细胞外信号调节激酶(mitogen activated protein kinases/extracellular signal-regulated kinase,MAPK/ERK)途径的入口处，它将细胞表面的受体与核内的转录因子相连接，调节细胞的生长和发育。吉非替尼、厄罗替尼、血管内皮抑素治

21、疗肺癌；30例可评价的病例20%获得PR17-AAG is a heat shock protein(Hsp)90 inhibitor thathas been identified as a potential therapeutic agent in thyroid cancer.In a phase I clinical trial of XL-184,平均无进展生存时间长达79周.大多数甲状腺癌属单克隆基因选择的恶性肿瘤，其中与甲状腺癌发病密切相关，较具代表性的基因主要包括BRAF、RAS及RET基因大约44%的甲状腺乳头状癌和约24%的甲状腺未分化癌会发生BRAF基因突变。Astra

22、 Zeneca 公司的ZD-6474/vandetanib2006年获欧洲罕见病药品委员会（COMP)肯定批准推荐，用于治疗甲状腺髓样癌In preclinical studies,17-AAG was found to reduce RET/PTC1 proteinlevels,induce cell death and increase the uptake of radioactive iodine into thyroid cancer cells1997,Hundahl et al.Like DTC,patients with metastatic disease do poorly

23、,with a 5 year survival of 6 months近十年来，新的分子靶向药物不断涌现，已有的分子靶向药物也不断增加新的适应症。nThyroid cancer is the most common malignancy of the endocrine systemn5-year disease-specific survival of patients with DTC with distant metastases is 50%(Shaha et al.1997,Hundahl et al.1998).nLike DTC,patients with metastatic

24、disease do poorly,with a 5 year survival of 50%(Hundahl et al.1998).nmedian survival of this group of patients is 6 months近十年来，新的分子靶向药物不断涌现，已有的分子靶向药物也不断增加新的适应症。median PFS 18 months伊马替尼治疗胃肠间质瘤。范德他尼（Vandetanib)ZD-6474是一种合成的苯胺喹啉化合物、口服的多靶点酪氨酸激酶抑制剂，抑制和肿瘤生长转移有关的细胞信号通路的多个因子，如上皮生长因子受体（EGFR)。如测定生化指标（降钙素、癌胚抗原

25、）评价疗效 1例（5%）完全缓解，5例（24%）病情缓解，3例（14%）病情稳定，12例（57%）病情稳定Phase II trial of sorafenib in advanced thyroid cancer小分子多靶点酪氨酸激酶抑制剂范得他尼治疗晚期甲状腺髓样癌Bodei L,Handkiewicz-Junak D,Grana C,et al.根据基因重排位置的不同，目前至少鉴定出11种RET/PTC基因PR in 13%,SD in 68%,progressive disease in 10%is ongoing.In a phase I clinical trial of XL-1

26、84,RET 基因定位于10号染色体，编码一种酪氨酸激酶受体超家族的跨膜蛋白Rixe et al 2007 renal cell carcinoma如测定生化指标（降钙素、癌胚抗原）评价疗效 1例（5%）完全缓解，5例（24%）病情缓解，3例（14%）病情稳定，12例（57%）病情稳定Six patients had SDs while rest of the patients progressed.RAF丝/苏氨酸激酶位于有丝分裂原活化蛋白激酶/细胞外信号调节激酶(mitogen activated protein kinases/extracellular signal-regulated kinase,MAPK/ERK)途径的入口处，它将细胞表面的受体与核内的转录因子相连接，调节细胞的生长和发育。Clin oncol,2007,25(18):6018RET 基因特异位点的点突变可以增强RET蛋白的转化能力，激发酪氨酸激酶自动磷酸化，诱导甲状腺滤泡旁细胞增生过度以致形成髓样癌