肿瘤分子靶向临床治疗.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。,肿瘤分子靶向治疗的发展,Treatment Modalities in Cancer,Mortality due Cancer has decreased:,-,Improved screening,-,Early diagnosis,-Improved treatment,Chemotherapy,?,Evolution of Chemotherapy,2005,肿瘤分子靶向治疗的概念,肿瘤分子靶向治疗的定义,就是针对性地瞄准一个靶位进行治疗“有的放矢的治疗”,肿瘤靶向治疗的三个层次,器官靶向,：,某种药物或方法只对某个器官的肿瘤有效，如肿瘤,的介入治疗、射频热疗等。,细胞靶向：,只针对某种类别的肿瘤细胞，药物或制剂进入体内,后可选择性地与这类细胞特异性地结合，从而消灭,肿瘤细胞，如,I,131,、希罗达、脂质体阿霉素等。,分子靶向,：,针对肿瘤细胞特有的受体，关键基因和调控分子为,靶点的治疗（阻断癌细胞信号传导通路中某一个分,子靶点），抑制肿瘤细胞生长的方法。,Capecitabine:,Tumor Activating 5-FU Prodrug,Intestine,Liver,5,-,DFCR,5,-,DFUR,CyD,5,-,DFCR,5,-,DFUR,5-,FU,Tumornormal tissue,Capecitabine,Thymidine,phosphorylase(TP),CyD,CE,5,-,DFCR,5,-deoxy-5-fluorocytidine;5,-DFUR,5,-deoxy-5-fluorouridine;,CyD,cytidine deaminase;minimal expression in BM,CEcarboxylesterase:preferentially expressed in liver,not in GI tract,Capecitabine,药代学靶向,肿瘤化疗是不是分子靶向治疗？,Non-selective,肿瘤化疗是不是分子靶向治疗？,攻击靶点的目标不同,细胞毒药物：,抑制增值迅速的肿瘤细胞的,DNA,合成,（杀灭作用）,分子靶向药物：,细胞癌变过程中的受体或转导过程,中关键性酶（改错作用）,药物开发程序不同,细胞毒药物：,筛选疗效靶点,分子靶向药物：,靶点设计疗效,肿瘤分子靶向治疗的特点,肿瘤分子靶向治疗的特点,靶向治疗并非肿瘤治疗所特有的,理想的靶向治疗是高度选择性的,靶向治疗也具有特异性的毒性反应,具有,特定的肿瘤分子标志物（,Marker,）,肿瘤分子靶向治疗的毒性,皮疹,(,痤疮样皮疹,),皮肤干燥,指甲改变,毛发改变,毛细血管扩张和色素沉着,EGFR抑制剂相关皮肤毒性,Estrogen Receptor:70-75%of breast cancers are ER+,HER-2:20-25%of breast cancers are HER-2+,Triple Negative:10-15%of breast cancers are ER/PR-and HER-2-,In Summary:A Paradigm for Tailored Medicine,Traditional Chemotherapy,Histological,profile of the tumor,Treatment decisions according to,population,prognostic and predictive factors,Non-selectivity,and,Cytotoxic,Targeted Therapy,Molecular,profile of the tumor,Treatment decisions according to,individual,prognostic and predictive factors,Selectivity,and,Non-cytotoxic,Potential Advantages,Less toxicity,Increased efficacy,Reduced drug resistance,肿瘤分子靶向治疗的分类,肿瘤分子靶向治疗的分类,按结构分类,NCI,分类,按靶点分类,肿瘤分子靶向治疗的分类,2004 年NCI分类,Small molecular drugs,小分子药物,Monocolonal,antibodies,单克隆抗体,Apoptosis-inducing drugs,抗凋亡药物,Angiogenesis,抗血管抑制剂,Cancer vaccines,肿瘤疫苗,Gene therapy,基因治疗,Current Targeted Agents Shopping List,Signal transduction/Cell-cycle inhibitors,-VX-680,-Vorinostst,-Decitabine,-Bortezomab*,-Dosatinib,-Stat-3 inhibitors,Gene therapy,-Wild type P53,-Antisense,Vaccines,-Tumor/dendritic cell,-Peptides,-Viral vaccine,Angiogenesis inhibitors,-Bevacizumab*,-Interferon-a/b*,-ZD6474/ZD2171,-LY317615,-Thrombospondin,Receptor-targeted therapy,-Multi-targeted,Imatinib mesylate*,Sunitinib*,Sorafenib*,Lapatinib,-Anti-HER-2,Trastuzumab*,-Anti-EGFR,Erlotinib*,Gefitinib,Cetuximab*,Panitumumab*,FDA,appoved,for one or more indication,Gefitinib,is no longer available in the USA except,under clinical study or when continuing on therapy,肿瘤分子靶向治疗的分类(推荐),肿瘤分子靶向治疗的实例,大肠癌的分子靶向治疗,Molecular Targeted Drugs in Colorectal Cancer,肿瘤分子靶向治疗的实例,Adjuvant,-Levamisol(+5FU),1990,-Leucovorin(+5FU),1994,-Oxaliplatin(FOLFOX),2005,-Capecitabine,2005,FDA:Agents Approved in Colon Cancer 2008,First-line,-Fluorouracil,5-FU,1962,-Leucovorin(+5FU),1991,-Irinotecan(+5FU/LV),2000,-Capecitabine,2001,-Oxaliplatin(+5FU/LV),2004,-Bevacizumab,2004,Refractory,-Irinotecan,1996,1998,-Oxaliplatin(+5FU/LV),2002,-Cetuximab,2004,-Panitumumab,2006,Cetuximab,Chimeric,IgG-1,against EGFR,30murine,3%HSR,ADCC?,Half-life:5day,Todays Issue,Molecular Targeted Drugs in Colorectal Cancer,Bevacizumab,humanized IgG-1,against VEGF,Optimal dose under,evaluation,FDA approved dose,5mg/kg,Half-life:20d+,Panitumumab,Fully human IgG-2,against EGFR,1%HSR,ADCC:No,Half-life:7.5day,手 术,转 移,辅助化疗,一线治疗,二线治疗,三线治疗,Bevacizumab,:,Randomised Trials in Progress,Patients with Metastatic Colorectal Cancer,NO16966,+XELOX,BIBB-C,+FOLFIRI,AVANT,E3200,+FOLFOX,TREE,+FOLFOX,AVF2107g,+IFL,NSABP C08,2nd line,1st line,Adjuvant,一,线,治,疗,一,线,治,疗,IFL+BEV IFL,一,线,治,疗,IFL+BEV IFL,一,线,治,疗,一,线,治,疗,FOLFIRI mIFL=CapeIRI,一,线,治疗,FOLFIRI+BEV FOLFIRI,一,线,治,疗,一,线,治,疗,FOLFOX+BEV FOLFOX,一,线,治,疗,XELOX=FOLFOX4,一,线,治,疗,XELOX/FOLFOX4+Bev,一,线,治,疗,NCCN Clinical Practice Guidelines in Oncology Colon Cancer v.2,00,8,FOLFOX,Irinotecan+Cetuximab,FOLFOX or CAPOX,+Bevacizumab,FOLFIRI,+,Bevacizumab,Single-Agent Irinotecan,Irinotecan,Cetuximab,FOLFOX,Irinotecan+Cetuximab,Irinotecan+Cetuximab,Single-Agent Irinotecan,FOLFOX,5-FU/LV*+,Bevacizumab,or,or,or,or,Irinotecan+Cetuximab,FOLFIRI,or,FOLFIRI,or,Single-Agent Irinotecan,Intensive Therapy,Minimal Therapy,First-Line Therapy,Second-Line Therapy,Third-Line,Therapy,Fourth-Line Therapy,*A treatment option for patients not able to tolerate oxaliplatin or irinotecan.,二,线,治,疗,二,线,治,疗,FOLFOX+BEV FOLFOX,Cetuximab,Chimeric,IgG-1,against EGFR,30%,murine,3%HSR,ADCC?,Half-life:5day,Todays Issue,Molecular Targeted Drugs in Colorectal Cancer,Bevacizumab,humanized IgG-1,against VEGF,Optimal dose under,evaluation,FDA approved dose,5mg/kg,Half-life:20d+,Panitumumab,Fully human IgG-2,against EGFR,1%HSR,ADCC:No,Half-life:7.5day,手 术,转 移,辅助化疗,一线治疗,二线治疗,三线治疗,Cetuximab:,Randomised Trials in Progress,Patients with Metastatic Colorectal Cancer,NCIC CO,.17,EPIC,After oxaliplatin,OPUS,+FOLFOX,PETACC-8,BOND,BOND,After irinotecan,CRYSTA,L,+FOLFIRI,INT 0147,3rd line,2nd line,1st line,Adjuvant,二,线,治,疗,二,线,治,疗,CET BSC,二,线,治,疗,二,线,治,疗,CPT-11+CET CPT-11,NCCN Clinical Practice Guidelines in Oncology Colon Cancer v.2,00,8,FOLFOX,Irinotecan+,Cetuximab,FOLFOX or CAPOX,+Bevacizumab,FOLFIRI,+,Bevacizumab,Single-Agent Irinotecan,Irinotecan,Cetuximab,FOLFOX,Irinotecan+,Cetuximab,Irinotecan+,Cetuximab,Single-Agent Irinotecan,FOLFOX,5-FU/LV*+,Bevacizumab,or,or,or,or,Irinotecan+,Cetuximab,FOLFIRI,or,FOLFIRI,or,Single-Agent Irinotecan,Intensive Therapy,Minimal Therapy,First-Line Therapy,Second-Line Therapy,Third-Line,Therapy,Fourth-Line Therapy,*A treatment option for patients not able to tolerate oxaliplatin or irinotecan.,KRAS,野生型,65%,KRAS,突变型,35%,一,线,治,疗,46.9%,FOLFIRI+Cetuxmab,38.7%,FOLFIRI,ORR,一,线,治,疗,FOLFIRI+CET FOLFIRI？,KRAS,野生型,58%,KRAS,突变型,42%,一,线,治,疗,一,线,治,疗,FOLFLOX+CET,FOLFLOX,NCCN Clinical Practice Guidelines in Oncology Colon Cancer v.2,00,8,FOLFOX,Irinotecan+Cetuximab,FOLFOX or CAPOX,+Bevacizumab,FOLFIRI,+,Bevacizumab,Single-Agent Irinotecan,Irinotecan,Cetuximab,FOLFOX,Irinotecan+Cetuximab,Irinotecan+Cetuximab,Single-Agent Irinotecan,FOLFOX,5-FU/LV*+,Bevacizumab,or,or,or,or,Irinotecan+Cetuximab,FOLFIRI,or,FOLFIRI,or,Single-Agent Irinotecan,Intensive Therapy,Minimal Therapy,First-Line Therapy,Second-Line Therapy,Third-Line,Therapy,Fourth-Line Therapy,*A treatment option for patients not able to tolerate oxaliplatin or irinotecan.,FOLFOX or CAPOX,+Cetuximab？,FOLFIRI,+Cetuxi,mab？5-FU/LV*+Cetuximab？,Will be changed,Cetuximab,Chimeric,IgG-1,against EGFR,30%,murine,3%HSR,ADCC?,Half-life:5day,Todays Issue,Molecular Targeted Drugs in Colorectal Cancer,Bevacizumab,humanized IgG-1,against VEGF,Optimal dose under,evaluation,FDA approved dose,5mg/kg,Half-life:20d+,Panitumumab,Fully human IgG-2,against EGFR,1%HSR,ADCC:No,Half-life:7.5day,Panitumumab,手 术,转 移,辅助化疗,一线治疗,二线治疗,三线治疗,Panitumumab:,Randomised Trials in Progress,Patients with Metastatic Colorectal Cancer,BSC,Panitumumab vs,Trial,Peeters,?,?,3rd line,2nd line,1st line,Adjuvant,二,线,治,疗,二,线,治,疗,Panitumumab BSC,Cetuximab,Chimeric,IgG-1,against EGFR,30%,murine,3%HSR,ADCC?,Half-life:5day,Todays Issue,Molecular Targeted Drugs in Colorectal Cancer,Bevacizumab,humanized IgG-1,against VEGF,Optimal dose under,evaluation,FDA approved dose,5mg/kg,Half-life:20d+,Panitumumab,Fully human IgG-2,against EGFR,1%HSR,ADCC:No,Half-life7.5day,Panitumumab,VEGF,+,EGFR,手 术,转 移,辅助化疗,一线治疗,二线治疗,三线治疗,Combination:,Randomised Trials in Progress,Patients with Metastatic Colorectal Cancer,Trial,BOND-2,PACCE,?,3rd line,2nd line,1st line,Adjuvant,二,线,治,疗,二,线,治,疗,Three drugs Two drugs,一,线,治,疗,一,线,治,疗,Three drugs=Two drugs,一,线,治,疗,Three drugs=Two drugs,Cetuximab,Chimeric,IgG-1,against EGFR,30%,murine,3%HSR,ADCC?,Half-life:5day,Todays Issue,Molecular Targeted Drugs in Colorectal Cancer,Bevacizumab,humanized IgG-1,against VEGF,Optimal dose under,evaluation,FDA approved dose,5mg/kg,Half-life:20d+,Panitumumab,Fully human IgG-2,against EGFR,1%HSR,ADCC:No,Half-life:7.5day,回,顾,性,研,究,K-RAS EXPRESSION,手 术,转 移,辅助化疗,一线治疗,二线治疗,三线治疗,EGFR Inhibitors and K-ras,in Patients with Metastatic Colorectal Cancer,Peeters Trial,Panitumumab vs BSC,OPUS,+FOLFOX,NCIC CO,.17,Cetuximab vs BSC,CRYSTA,L,+FOLFIRI,?,2nd line or 3rd line,1st line,Adjuvant,0.011,0.064,p-value,ERBITUX+FOLFOX,FOLFOX,ERBITUX+FOLFOX,FOLFOX,7.7,7.2,7.2,7.2,PFS(months),0.57,0.931,HR,0.016,0.62,p-value,61,37,46,36,ORR(%),73,61,168,169,N,KRAS,野生型,ITT,人群,一,线,治,疗,Cetuximab First Line Metastatic CRC:CRYSTAL Trial,FOLFIRI+CET FOLFIRI,0.011,0.064,p-value,ERBITUX+FOLFOX,FOLFOX,ERBITUX+FOLFOXFOLFOX,7.7,7.2,7.2,7.2,PFS(months),0.57,0.931,HR,0.016,0.62,p-value,61,37,46,36,ORR(%),73,61,168,169,N,KRAS,野生型,ITT,人群,一,线,治,疗,Cetuximab First Line Metastatic CRC:OPUS Trial,FOLFOX+CET FOLFOX,一,线,治,疗,K-RAS EXPRESSION,二,线,治,疗,K-ras 野生型：CET BSC,二,线,治,疗,K-ras突变型：CET BSC,KRAS Status and Response to Panitumumab,二,线,治,疗,K-ras 野生型：Pan BSC,Key Toxicities of Cytotoxic and Targeted Therapies,Dermatologic,Hand-foot syndrome,Hyperpigmentation,Gastrointestinal,Diarrhea,Nausea/vomiting,Stomatitis/mucositis,Myelosuppression,Neurotoxicity,Acute,Delayed,Gastrointestinal,Diarrhea,Nausea/vomiting,Myelosuppression,Hypersensitivity,Gastrointestinal,Diarrhea,Nausea/vomiting,Myelosuppression,Fatigue,Alopecia,Febrile neutropenia,Gastrointestinal,Mucositis,Diarrhea,Dermatologic,Hand-foot syndrome,Myelosuppression,Capecitabine,Oxaliplatin,Irinotecan,5-FU/LV,Dermatologic,Acneiform rash,Infusion reactions,Interstitial lung disease(rare),Hypomagnesemia,Cetuximab,Dermatologic,Acneiform rash,Infusion reactions,Pulmonary Fibrosis(rare),Diarrhea,Hypomagnesemia,Cardiovascular,Hypertension,Bleeding,Thrombosis,Delayed wound healing,GI perforation,Proteinuria/nephrotic syndrome,Panitumumab,Bevacizumab,Adrucil,prescribing information.Kalamazoo,Mich:Pharmacia Camptosar,prescribing information.New York,NY:Pharmacia,Xeloda prescribing information.Nutley,NJ:Roche Laboratories;2005;,Avastin,prescribing information.South San Francisco,Calif:Genentech,Inc;2005;Erbitux,prescribing information.Princeton,NJ:Bristol-Myers Squibb Company;2005;Vectibix prescribing information.Thousand Oaks,CA:AMGEN Company;2006.,Wholesale Drug Costs,(75kg,1.8m2 atient,two weeks Rx),5-FU,500mg/m2,9,Leucovorin,500mg/m2,61,Xeloda,2000mg/m2,853,Camptosar,180mg/kg,2608,Eloxatin,85mg/m2,2983,Avastin,5mg/kg,2750,Erbitux,250mg/m2,5760,Vectibix,6mg/kg,5800,肿瘤分子靶向治疗的挑战,肿瘤分子靶向治疗的挑战,对,胰腺癌和胶质瘤,细胞的约 21000个基因进行了测序分析，结果显示在胰腺癌发生突变的基因平均为,63,个，胶质瘤为,47,个,EMB,.“鸡尾酒”式疗法是发展趋势,