肿瘤分子靶向治疗 Oct 19,2009.ppt

1、Molecular targeted therapy,Rui-hua Xu 徐瑞华 Sun Yat-sen University Cancer Center Tel: 020-8734 3468,Parkin et al. CA Cancer J Clin 2005,Estimated New Cancer Cases and Deaths in 2002,内科治疗可以获得根治的肿瘤,NHL,Historical improvements of Therapy in Advanced CRC,Van Cutsem/Hoff JCO 2000,Doulliard Lancet 2000,14.8

2、,Saltz NEJM 2000,Douillard Lancet 2000,Saltz NEJM 2000,Median overall survival (months),12.6,14.1,Supportive Care,5-FU bolus,5-FU infusion,Irinotecn/5-FU bolus,6.0,肿瘤内科学的进步,抗肿瘤药物及支持治疗药物的发展 肿瘤内科治疗理念的进步 GCP原则的应用及循证医学 多学科综合治疗的广泛应用 专科化及规范化治疗的广泛实施 分子指标的发现及个体化治疗,抗癌药物发展历史概括,20世纪下半叶 以细胞毒药物为主，新的药物不断出现 20世纪末2

3、1世纪 细胞毒药物的继续发展 分子靶向药物的发展 免疫相关治疗及基因治疗,Anatomy 16th Century Advance,Molecular Anatomy 21st Century Advance,从根本上改变肿瘤治疗的模式靶向性治疗,Cancer Research is evolving rapidly From empiric to mechanistic - New strategies abound- The public is VERY interested,ON,OFF,Tumor Cell Survival andGrowth,Tumor Cell Growth Ar

4、rest and Cancer Regression,Searching for the Critical Switch in Cancer,What is Targeted Therapy?,Treatment designed to modulate a specific signaling event that is thought to have a critical role in the survival, proliferation, invasion or metastasis of a specific cancer cell. 292 different genetic e

5、vents have been shown happen in tumors (5% frequency in tumors) All genetic events are potential targets for therapy may not be possible to develop drugs for all targets,Targeted Cancer Therapies,Selectivetargets tumor cells (选择性） Fewer systemic toxicities predicted （毒性低） Dosing can be adjusted to b

6、iologic activity of the drug （生物活性剂量） May improve quality of life during treatment （提高生活质量） Dramatic responses in select subsets of patients （对部分病例有特效）,Signal transduction occurs in complex integrated network,DESIGN A NEWDRUG TO BLOCK CANCER,Metastatic GIST before and after Kinase Inhibition,Baselin

7、e Pre-Imatinib,1 month on Imatinib,Avid PET Uptake,No PET Uptake,Developmental Therapeutics: Molecular Therapeutics,Antiangiogenic or Antimetastatic Agents Cell Cycle Inhibitors mTOR inhibitors Gene Therapy/Antisense Strategies Receptor-Targeted Antibodies/Ligands Tyrosine Kinase Inhibitors Vascular

8、 Targeting : AZD2171，VEGF trap Pro-Apoptotic Agents,Developmental Therapeutics: Immunotherapy,Antibodies Cell-Based Therapy Cytokines Vaccines Other: developmental therapeutics: immunotherapy,已上市的靶向治疗药物,Rituxan：B细胞淋巴瘤, anti-CD20 moAb Herceptin：Her2高表达的乳腺癌 Gleevec：CML，GIST Irressa、Tarceva：NSCLC Bevac

9、izumab：CRC、NSCLC、Breast Ca C225：CRC、H8:994-1003.,Mean tumor volume (mm3),Days,0,安慰剂 爱必妥 伊立替康 爱必妥 + 伊立替康,Initiation of treatment,10,20,30,40,50,0,1000,2000,3000,4000,BOND study - Study design,Randomization,ERBITUX initial 400 mg/m2 2-h infusion then 250 mg/m2 1-h infusion weekly + Irinotecan* n = 218

10、,ERBITUX initial 400 mg/m2 2-h infusion then 250 mg/m2 1-h infusion weekly n = 111,Patients with EGFR-expressing mCRC failing, or within 3 months of, irinotecan-based therapy,Progressive disease,ERBITUX + Irinotecan* n = 56,Cunningham et al. N Engl J Med 2004; 351:337-345,*Irinotecan given at same d

11、ose as the last prior treatment,BOND studyResponse rate,Cunningham et al. N Engl J Med 2004; 351:337-345.,ERBITUX + irinotecan(n=218) ERBITUX (n=111),Percentage (%),23*,11*,32*,56*,* p=0.0074; * p0.001; intent to treat,BOND studyERBITUX + irinotecan prolongs time to progression,Patients free of prog

12、ression (%),Time to progression (months),Cunningham et al. N Engl J Med 2004; 351:337-345.,p0.001,ERBITUX + irinotecan (n=218) ERBITUX (n=111),C225治疗前 2006-10-16,C225+CPT-11治疗1程后 2006-11-28,C225+CPT-11治疗2程后 2007-1-17,A CRC case treated with BOND schedule in SYSUCC,C225治疗前,C225+CPT-11治疗1程后,C225+CPT-1

13、1治疗2程后,A CRC case treated with BOND schedule in SYSUCC,Mendelsohn, J. et al. J Clin Oncol; 21:2787-2799 2003,Inhibition of signaling pathways by anti-epidermal growth factor receptor (EGFR) therapies,BR.21 Study Design,RANDOM I SE,2:1 randomisation Endpoint: OS Treatment till PD,NSCLC 1 or 2 prior c

14、hemo regimens (including single agents if 70) PS 0 - 3,Shepherd et al, NEJM 2005; 353: 123 - 32,BR 21: Overall Survival,Shepherd et al, NEJM 2005; 353: 123 - 32,Molecular Targeting of Breast Cancer,免疫组织化学法IHC色素原位杂交法CISH 荧光原位杂交法FISH,操作和判读方法与IHC相似 同时可以进行组织学评估 与FISH检测结果相关性高 国内有多家中心可以进行 检测成本约1700 RMB/例,

15、准确、重复性好与疗效相关性好 需置备荧光显微镜等设备 操作者需非常有经验 检测费用较高3000 RMB/例 国内可此项检测单位少,HER2检测方法,成熟的技术 快速同时得到许多病例结果 读片较为简单 成本80120RMB/例,赫赛汀辅助治疗显著改善Breast Ca 无进展生存时间,87%,85%,67%,75%,%,ACTH,ACT,随机分组后年,B-31/N9831,NEvents ACT1679261 ACTH1672134,HR=0.48, 2P=3x10-12,VEGF and Tumor Growth,VEGF stimulate tumor angiogenesis Tumor

16、blood vessels created by VEGF are abnormal - Leaky and twisted -Improperly matured VEGF may inhibit the tumoral immune response VEGF is overexpressed in a broad range of human tumors and is associated with poor clinical outcomes.,Folkman J. N Engl J Med 1971;285:11826,In the absence of vascularisati

17、on, solid tumours remain dormant and 23mm3 in size, with size being limited by the ability of oxygen and nutrients to diffuse into the tumour,Folkmans Hypothesis 1971:,VEGF: Key factor in Tumor angiogenesis,Transcription,2. Anti-Receptor mAbs,1. Ligand Sequestration: mAbs, Soluble Receptors BEV, VEG

18、F-TRAP,3. Tyrosine Kinase Inhibitors,4. Inhibitors of Downstream signaling events,5. VEGFR Antisense/Ribozyme,Targeting the VEGF Pathway,GW786034, AZD2171 PTK787,PI3K,AKT,RAS,MAPK,Grb2,Src,P,P,P,P,Phase III trial of IFL bevacizumab survival,Probability of survival,1.0 0.8 0.6 0.4 0.2 0,010203040,Sur

19、vival (months),IFL + placebo IFL + bevacizumab,Median survival (months)IFL + placebo: 15.6 vs IFL + bevacizumab: 20.3 HR: 0.66, p=0.00004,HR = hazard ratio,Hurwitz H, et al. N Engl J Med 2004;350:233542,Response rate and duration,CR = complete response PR = partial response,Hurwitz H, et al. N Engl

20、J Med 2004;350:233542,VEGF Receptor Tyrosine Kinase Inhibitors,57,BAY 43-9006: A Novel RAF Kinase and VEGFR Inhibitor That Combines Two Anticancer Activities*,Tumor cell,Blood vessel cell,BAY 43-9006 inhibited tumor cell proliferation by targeting the RAF/MEK/ERK signaling pathway at the level of RA

21、F kinase.,BAY 43-9006 demonstrated an antiangiogenic effect by targeting the receptor tyrosine kinases VEGFR-2 and PDGFR and their associated signaling cascades.,*Both anticancer activities were observed in preclinical models.,Wilhelm S et al. Clin Cancer Res. 2003;9(suppl). Abstract A78.,B. 3T3: VE

22、GFR-2 receptor phosphorylation,A. HUVEC: VEGFR-2 receptor phosphorylation,C. HAoSMC: PDGFR-b (pTyr-857) receptor phosphorylation,Wilhelm S et al. Clin Cancer Res. 2003;9(suppl). Abstract A78.,BAY 43-9006 Inhibited VEGFR-2 and PDGFR- Receptor Phosphorylation,BAY 43-9006 inhibits two key receptor tyro

23、sine kinases (RTKs) involved in tumor progression and angiogenesis,索拉非尼抗肿瘤作用机制：抑制肿瘤血管生成,通过抑制RTK,VEGFR-2,PDGFR-B激酶活性而抑制肿瘤血管生成,Targets研究设计 in RCC,TARGETs: 索拉非尼组无疾病进展生存期显著延长达一倍*,*独立评估，数据截至日期2005-1-28 Data from Escudier B. ECCO; November 3, 2005; Paris, France.,Imatinib Triples Overall Survivalin GIST Patients but Resistance Occurs,Historical Control,Imatinib 400 mg or 800 mg,Metastatic GIST bef