经典癌症治疗进展.ppt

癌症治疗进展,北京协和医院肿瘤内科,本世纪最初10年医学科学领域 10项重大进展,人类基因图谱的成功绘制 信息技术更多应用于医学领域 禁烟运动见成效 心脏病死亡率下降 干细胞研究进展 肿瘤靶向治疗新药的出现 药物联合治疗改善HIV感染者生存 微创和机器人技术革新外科手术 发现激素替代疗法增加心脏疾病和癌症风险 功能性磁共振成像用于探测脑部信息,ABC news、MedPage Today 2010,ASCO2009 年临床肿瘤学的 重大进展,EGFR突变能预测NSCLC的疗效 曲妥珠单抗改善Her2阳性胃癌的生存 西妥昔单抗联合化疗改善晚期头颈部癌的预后 贝伐单抗对脑胶质母细胞瘤有效 FDA批准伊维莫斯和贝伐单抗+干扰素治疗晚期肾癌,嘌呤,核苷酸,嘧啶,6巯基嘌呤 硫鸟嘌呤,脱氧核苷酸,DNA,RNA （tRNA、mRNA、核蛋白体）,蛋白质,微管,酶类,抑制嘌呤合成,抑制核苷酸转变,氨甲喋呤,抑制嘌呤合成,抑制dTMP合成,氟尿嘧啶,阿糖胞苷,抑制DNA聚合酶,抑制RNA功能,博莱霉素,损伤DNA,阻碍修复,烷化剂、顺铂、丝裂霉素,与DNA交叉联接,三尖杉酯碱,抑制蛋白质合成,L门冬酰胺酶,VP16、HCPT、ADM,抑制TOPO酶或,放线菌素D,抑制RNA合成,嵌入DNA,长春碱类,促使微管解聚,紫杉类,促使微管聚合,羟基脲、 脱氧胞苷,抑制核苷酸还原酶,化疗作用机理,4,5,Targeted Therapies,Erlotinib,Chemotherapy,Inhibition of programmed cell death (apoptosis),Tumor cell proliferation,Tumor cell invasion metastasis,Development of tumor vasculature (angiogenesis),迫切需要一种效/副比理想的新型药物,靶向治疗(Targeted Therapy; Novel Agent) 主要针对肿瘤细胞内一些特有的生物学标志或信号传导通道中重要的蛋白质或酶(表皮生长因子受体-酪氨酸激酶) 为了与传统的细胞毒药物(cytotoxic drugs)区别，这类药物被称为细胞增殖抑制药(cytostatic drugs),分子靶向药物,作用于肿瘤细胞的表皮生长因子受体（EGFR）的药物： Iressa，Tarceva，lapatinib，neratinib， Herceptin，Cetuximab，panitumumab， 作用于血管细胞的血管表皮生长因子（VEGF） 的药物：Avastin等，pazopanib 多靶点药物 ：Sunitinib， Sorafenib 等,8,分子靶向药物,Bcr-abl TKI:伊马替尼 mammalian target of rapamycin (mTOR)抑制剂，如Temsirolimus和Everolimus IGF-1抑制剂：Figitumumab 蛋白酶体抑制剂：Bortezomib poly(ADPribose) polymerase (PARP) inhibitors：Olaparib，BSI-201，AG014699,9,分子靶向药物,肿瘤相关抗原 抗CD20单抗-利妥昔单抗Rituxan 抗CD52-Alemtuzumab 阿伦单抗 抗CD33单抗-Gemtuzumab ozogamicin 用靶向抗体作载体，将药物运送到肿瘤细胞周围，高效力杀死肿瘤细胞，如： Zevalin-抗CD20单抗标联铟-111或钇-90 Bexxar-抗CD20单抗标联I-131 T-DM1-herceptin联合化疗药物,10,EGFR 在特定人类癌症中的表达情况,Salomon (1995); Chow (1997),31-48%,膀胱癌,Salomon (1995); Watanabe (1996);Rieske (1998),40-63%,神经胶质瘤,Bartlett (1996); Fischer-Colbrie (1997),35-70%,卵巢癌,Klijn (1992); Bucci (1997);Walker (1999),14-91%,乳腺癌,Salomon (1995); Yoshida (1997),50-90%,肾癌,Fujino (1996); Fontanini (1998),40-90%,非小细胞肺癌,Salomon (1995); Uegaki (1997),30-95%,胰腺癌,Salomon (1995); Grandis (1996),95-100%,头颈部肿瘤,Salomon (1995); Messa (1998),72-82%,结直肠癌,参考文献,肿瘤的 EGFR 表达百分比,肿瘤类型,11,EGFR 表达的临床意义,Neal (1985),差,膀胱癌,Sainsbury (1985),差,乳腺癌,Volm (1998) Veale (1993) Ohsaki (2000) Pavelic (1993),增加,降低OS,差 差,非小细胞肺癌,Dong (1998) Yamanaka (1993),降低OS,差,胰腺癌,Grandis (1998) Maurizi (1996),降低 DFS，降低OS,差,头颈部癌,Mayer (1993) Hemming (1992),增加,差,结直肠癌,参考文献,转移风险,生存,预后,肿瘤类型,DFS = disease-free survival; OS = overall survival;,12,EGFR 信号通路,EGFR 可被配体（ EGF和 TGF-）激活 EGFR活化可导致受体的二聚体化 受体的二聚体化启动了细胞内信号级联反应和基因活化，从而促进细胞周期的进程,Baselga. Eur J Cancer 2001;37 Suppl 4:S16-S22.,13,EGFR靶点的重要作用,*抑制细胞凋亡 *促进细胞增殖 *抑制细胞分化 *促进血管生成 *促进细胞的转移和侵袭,Baselga. Eur J Cancer 2001: 37 Suppl 4:S16-S22.,14,Kinase inhibitor,Activation of EGFR plays an essential role in cellular survival and proliferation programs,EGF TGF Amphiregulin -cellulin HB-EGF,Tyrosine - kinase domain,EGFR (ErbB) family and ligands,16,EGFR靶向药物作用机制,Erbitux,Herceptin,erlotinib,gefitinib,Signaling Cell Division/Tumor Growth,lapatinib,Erbitux,Herceptin,17,肿瘤血管,Adapted from Bergers G, et al. Nature 2002;3:40110,小肿瘤 (12mm) 无血管 休眠,大肿瘤 血管 转移潜能,18,19,Tumors Progressively Make More Angiogenesis Stimulators,Relf et al., Cancer Research, 57:953, 1997,bFGF,bFGF VEGF,bFGF VEGF PDGF,bFGF VEGF PDGF IL-8,The VEGF Family and Its Receptors,VEGFR-3,VEGFR-2,VEGFR-1,Angiogenesis,Angiogenesis,Lymphangiogenesis,lymphangiogenesis,PlGF,VEGF-A,VEGF-B,VEGF-C,VEGF-D,NRP-1 (neuropilin),Unclear but likely involved in tumor growth (Non-RTK),PlGF = Placental growth factor; RTK = Receptor tyrosine kinase.,Dvorak. J Clin Oncol. 2002; 20:4368; Ferrara et al. Nat Med. 2003; 9:669.,Bevacizumab,21,Wilhelm S, et al. Clin Cancer Res 2004;64:7099109,Sorafenib: targets both tumour cell and vascular compartments,Tumour cell,Endothelial cell or pericyte (vascular),Angiogenesis: differentiation proliferation migration tubule formation,VEGFR-2,PDGFR-,MEK,Apoptosis,Proliferation,PDGF,VEGF,Survival,Ras,ERK,MEK,Apoptosis,PDGF,VEGF,Paracrine stimulation,KIT/Flt-3/RET,Mitochondria,Mitochondria,Mcl-1,HIF,Sorafenib,Sorafenib,Sorafenib,Nucleus,HIF = hypoxia inducible factor; VEGF = vascular endothelial growth factor VEGFR = VEGF receptor; PDGF = platelet-derived growth factor PDGFR = PDGF receptor; Mcl-1 = myeloid cell leukaemia-1,A multi-kinase inhibitor of serine/threonine kinases: C-Raf (Raf-1) and B-Raf-1 receptor tyrosine kinases: VEGFR-2, VEGFR-3, PDGFR-, Flt-3, and c-KIT,22,肾细胞癌 (RCC):治疗靶点,Kaelin WG. Nat Rev Cancer 2002;2:67382,VHL,HIF,=,VEGFR,EGFR,PDGFR,Raf,mTOR,Erlotinib,Temsirolimus,mTOR = mammalian target of rapamycin EGFR = endothelial growth factor receptor VEGFR = VEGF receptor; PDGFR = PDGF receptor,Raf,PDGF,VEGF,TGF-,23,Vertical Target anti-tumor,Cetuximab,Bevacizumab,ZD6474,Lapatinib,Sorafenib,Rapamycin,AntiCyclinD1?,Anti Tumor stem cell?,29,NSCLC靶向治疗进展,RR 15% 20-30% 2372% 40%,1960s 1970-80s 1990s 2000,5-FU,ECF,LFEP 5-FU+/-LV/P,FAMTX EAP, ELF FUP,FAM FAP UFTM,紫杉类（泰索帝 ） 奥沙利铂（乐沙定） 卡培他滨, S-1 伊立替康, 靶向药物,进展期胃癌的治疗历程,OS 4-5m 6-7m 6m 8 m,生 物 靶 向 治 疗,FAM = 5-FU, doxorubicin, mitomycin C; FAMTX = 5-FU, doxorubicin, methotrexate; ECF = epirubicin, cisplatin, 5-FU; CF = cisplatin, 5-FU,1. Wagner A, et al. Cochrane Database Syst Rev 2005;2:CD004064. 2. Kim NK, et al. Cancer 1993;71:38133818. 3. Ohtsu A, et al. J Clin Oncol 2003;21:5459. 4. Wils JA, et al. J Clin Oncol 1991;9:827831. 5. Waters JS, et al. Br J Cancer 1999;80:269272. 6. Vanhoefer U, et al. J Clin Oncol 2000;18:26482657. 7. Cocconi G, et al. Ann Oncol 2003;14:12581263. 8. Ross P, et al. J Clin Oncol 2002;20:19962004. 9. Webb A, et al. J Clin Oncol 1997;15:261267.,ITT, 治疗意向人群; wt, 野生型; LLD, 仅有肝转移患者,mCRC治疗的有效率大幅提高: 患者选择和个体化治疗的影响,1. Folprecht et al. ESMO 2008; 2. Van Cutsem et al. ESMO 2008; 3. Bokemeyer et al. ASCO 2008; 4. Van Cutsem et al. ASCO 2008; 5. Saltz et al. WCGIC 2007,Tailored therapy new era in mCRC,Cetuximab in mCRC: Consistent efficacy across all lines of therapy,1st-line (115,722),3rd-line (36,837),2nd-line (57,131),Cetuximab + FOLFIRI/FOLFOX CRYSTAL / OPUS PFS RR Cure,Stage IV mCRC patients in Europe: 209,690*,*IARC,33,CRC药物治疗进展历程,中位生存时间,35 30 25 20 15 10 5 0,Months,5-FU,最佳支持治疗,依立替康,卡培他滨,奥沙利铂,1980 1985 1990 1995 2000 2010,安维汀,Advances in OS in RCC,35,2004年发现淋巴结阴性患者预后与 HER2状态密切相关,p=0.0001 Cumulative disease recurrence curves,Sun JM. Cancer 2004;101:251622,累计复发事件,0.3 0.2 0.1 0,0 20 40 60 80 100,月,HER2阳性患者平均风险曲线,HER2 阴性患者平均风险曲线,最低风险曲线,36,Bevacizumab in HER2 negative MBC - First-line Studies,Bevacizumab dose at 15mg/kg q3 weeks except for low-dose arm in AVADO,Miller et al. NEJM 2007, 357: 2666-76 Miles et al. SABCS 2009 Robert et al. ASCO 2009,37,索拉菲尼治疗肝癌临床研究,38,昨天、今天 千篇一律的治疗,未来 度身定制的治疗,NSCLC EGFR突变阳性 与阴性患者的缓解率,