《癌癥治療進(jìn)展》PPT課件.ppt

1、癌癥治療進(jìn)展,北京協(xié)和醫(yī)院腫瘤內(nèi)科,本世紀(jì)最初10年醫(yī)學(xué)科學(xué)領(lǐng)域10項(xiàng)重大進(jìn)展,人類基因圖譜的成功繪制 信息技術(shù)更多應(yīng)用于醫(yī)學(xué)領(lǐng)域 禁煙運(yùn)動(dòng)見成效 心臟病死亡率下降 干細(xì)胞研究進(jìn)展 腫瘤靶向治療新藥的出現(xiàn) 藥物聯(lián)合治療改善HIV感染者生存 微創(chuàng)和機(jī)器人技術(shù)革新外科手術(shù) 發(fā)現(xiàn)激素替代療法增加心臟疾病和癌癥風(fēng)險(xiǎn) 功能性磁共振成像用于探測(cè)腦部信息,ABC news、MedPage Today 2010,ASCO2009 年臨床腫瘤學(xué)的重大進(jìn)展,EGFR突變能預(yù)測(cè)NSCLC的療效 曲妥珠單抗改善Her2陽(yáng)性胃癌的生存 西妥昔單抗聯(lián)合化療改善晚期頭頸部癌的預(yù)后 貝伐單抗對(duì)腦膠質(zhì)母細(xì)胞瘤有效 FDA批準(zhǔn)伊

2、維莫斯和貝伐單抗+干擾素治療晚期腎癌,嘌呤,核苷酸,嘧啶,6巰基嘌呤 硫鳥嘌呤,脫氧核苷酸,DNA,RNA （tRNA、mRNA、核蛋白體）,蛋白質(zhì),微管,酶類,抑制嘌呤合成,抑制核苷酸轉(zhuǎn)變,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,博萊霉素,損傷DNA,阻礙修復(fù),烷化劑、順鉑、絲裂霉素,與DNA交叉聯(lián)接,三尖杉酯堿,抑制蛋白質(zhì)合成,L門冬酰胺酶,VP16、HCPT、ADM,抑制TOPO酶或,放線菌素D,抑制RNA合成,嵌入DNA,長(zhǎng)春堿類,促使微管解聚,紫杉類,促使微管聚合,羥基脲、 脫氧胞苷,抑制核苷酸還原酶,化療作用機(jī)理,4,5,Ta

3、rgeted Therapies,Erlotinib,Chemotherapy,Inhibition of programmed cell death (apoptosis),Tumor cell proliferation,Tumor cell invasion metastasis,Development of tumor vasculature (angiogenesis),迫切需要一種效/副比理想的新型藥物,靶向治療(Targeted Therapy; Novel Agent) 主要針對(duì)腫瘤細(xì)胞內(nèi)一些特有的生物學(xué)標(biāo)志或信號(hào)傳導(dǎo)通道中重要的蛋白質(zhì)或酶(表皮生長(zhǎng)因子受體-酪氨酸激酶) 為了

4、與傳統(tǒng)的細(xì)胞毒藥物(cytotoxic drugs)區(qū)別，這類藥物被稱為細(xì)胞增殖抑制藥(cytostatic drugs),分子靶向藥物,作用于腫瘤細(xì)胞的表皮生長(zhǎng)因子受體（EGFR）的藥物： Iressa，Tarceva，lapatinib，neratinib， Herceptin，Cetuximab，panitumumab， 作用于血管細(xì)胞的血管表皮生長(zhǎng)因子（VEGF） 的藥物：Avastin等，pazopanib 多靶點(diǎn)藥物 ：Sunitinib， Sorafenib 等,8,分子靶向藥物,Bcr-abl TKI:伊馬替尼 mammalian target of rapamycin (mT

5、OR)抑制劑，如Temsirolimus和Everolimus IGF-1抑制劑：Figitumumab 蛋白酶體抑制劑：Bortezomib poly(ADPribose) polymerase (PARP) inhibitors：Olaparib，BSI-201，AG014699,9,分子靶向藥物,腫瘤相關(guān)抗原 抗CD20單抗-利妥昔單抗Rituxan 抗CD52-Alemtuzumab 阿倫單抗 抗CD33單抗-Gemtuzumab ozogamicin 用靶向抗體作載體，將藥物運(yùn)送到腫瘤細(xì)胞周圍，高效力殺死腫瘤細(xì)胞，如： Zevalin-抗CD20單抗標(biāo)聯(lián)銦-111或釔-90 Bexx

6、ar-抗CD20單抗標(biāo)聯(lián)I-131 T-DM1-herceptin聯(lián)合化療藥物,10,EGFR 在特定人類癌癥中的表達(dá)情況,Salomon (1995); Chow (1997),31-48%,膀胱癌,Salomon (1995); Watanabe (1996);Rieske (1998),40-63%,神經(jīng)膠質(zhì)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%

7、,腎癌,Fujino (1996); Fontanini (1998),40-90%,非小細(xì)胞肺癌,Salomon (1995); Uegaki (1997),30-95%,胰腺癌,Salomon (1995); Grandis (1996),95-100%,頭頸部腫瘤,Salomon (1995); Messa (1998),72-82%,結(jié)直腸癌,參考文獻(xiàn),腫瘤的 EGFR 表達(dá)百分比,腫瘤類型,11,EGFR 表達(dá)的臨床意義,Neal (1985),差,膀胱癌,Sainsbury (1985),差,乳腺癌,Volm (1998) Veale (1993) Ohsaki (2000) Pa

8、velic (1993),增加,降低OS,差 差,非小細(xì)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,頭頸部癌,Mayer (1993) Hemming (1992),增加,差,結(jié)直腸癌,參考文獻(xiàn),轉(zhuǎn)移風(fēng)險(xiǎn),生存,預(yù)后,腫瘤類型,DFS = disease-free survival; OS = overall survival;,12,EGFR 信號(hào)通路,EGFR 可被配體（ EGF和 TGF-）激活 EGFR活化可導(dǎo)致受體的二聚體化 受體的二聚體化啟動(dòng)了細(xì)胞內(nèi)信號(hào)

9、級(jí)聯(lián)反應(yīng)和基因活化，從而促進(jìn)細(xì)胞周期的進(jìn)程,Baselga. Eur J Cancer 2001;37 Suppl 4:S16-S22.,13,EGFR靶點(diǎn)的重要作用,*抑制細(xì)胞凋亡 *促進(jìn)細(xì)胞增殖 *抑制細(xì)胞分化 *促進(jìn)血管生成 *促進(jìn)細(xì)胞的轉(zhuǎn)移和侵襲,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 Amphi

10、regulin -cellulin HB-EGF,Tyrosine - kinase domain,EGFR (ErbB) family and ligands,16,EGFR靶向藥物作用機(jī)制,Erbitux,Herceptin,erlotinib,gefitinib,Signaling Cell Division/Tumor Growth,lapatinib,Erbitux,Herceptin,17,腫瘤血管,Adapted from Bergers G, et al. Nature 2002;3:40110,小腫瘤 (12mm) 無(wú)血管 休眠,大腫瘤 血管 轉(zhuǎn)移潛能,18,19,Tumor

11、s Progressively Make More Angiogenesis Stimulators,Relf et al., Cancer Research, 57:953, 1997,bFGF,bFGF VEGF,bFGF VEGF PDGF,bFGF VEGF PDGFIL-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-

12、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 tumo

13、ur 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,

14、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 kin

15、ases: C-Raf (Raf-1) and B-Raf-1 receptor tyrosine kinases: VEGFR-2, VEGFR-3, PDGFR-, Flt-3, and c-KIT,22,腎細(xì)胞癌 (RCC):治療靶點(diǎn),Kaelin WG. Nat Rev Cancer 2002;2:67382,VHL,HIF,=,VEGFR,EGFR,PDGFR,Raf,mTOR,Erlotinib,Temsirolimus,mTOR = mammalian target of rapamycinEGFR = endothelial growth factor receptorVEGF

16、R = 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靶向治療進(jìn)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 F

17、AP UFTM,紫杉類（泰索帝 ） 奧沙利鉑（樂(lè)沙定） 卡培他濱, S-1 伊立替康, 靶向藥物,進(jìn)展期胃癌的治療歷程,OS 4-5m 6-7m 6m 8 m,生 物 靶 向 治 療,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,

18、 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

19、Oncol 2002;20:19962004. 9. Webb A, et al. J Clin Oncol 1997;15:261267.,ITT, 治療意向人群; wt, 野生型; LLD, 僅有肝轉(zhuǎn)移患者,mCRC治療的有效率大幅提高: 患者選擇和個(gè)體化治療的影響,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 th

20、erapy 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/FOLFOXCRYSTAL / OPUS PFSRRCure,Stage IV mCRC patients in Europe: 209,690*,*IARC,33,CRC藥物治療進(jìn)展歷程,中位生存時(shí)間,35 30 25 20 15 10 5 0,Months,5-FU,最

21、佳支持治療,依立替康,卡培他濱,奧沙利鉑,1980 1985 1990 1995 2000 2010,安維汀,Advances in OS in RCC,35,2004年發(fā)現(xiàn)淋巴結(jié)陰性患者預(yù)后與HER2狀態(tài)密切相關(guān),p=0.0001 Cumulative disease recurrence curves,Sun JM. Cancer 2004;101:251622,累計(jì)復(fù)發(fā)事件,0.3 0.2 0.1 0,020406080100,月,HER2陽(yáng)性患者平均風(fēng)險(xiǎn)曲線,HER2 陰性患者平均風(fēng)險(xiǎn)曲線,最低風(fēng)險(xiǎn)曲線,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,索拉菲尼治療肝癌臨床研究,38,昨天、今天 千篇一律的治療,未來(lái) 度身定制的治療,NSCLC EGFR突變陽(yáng)性與陰性患者的緩解率,43,NSCLC-EGFR突變,