恶性肿瘤的个体化治疗-.ppt

单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,个体化疗：,在体水平动物模型,细胞水平药物敏感实验,基因水平DNA水平,RNA水平,2004 年,ASCO,预测：,未来5-10年将是由当今标准化疗向个体化疗的过渡期,2005 年,ASCO,预测：,药物基因指导下“个体化疗”是肿瘤化疗的一场革命,200,62007 年,ASCO,：,肿瘤的化疗已经迈入“个体化疗”的新时代,“药物相关基因指导下个体化 疗”,Pharmacogenetics/Pharmacogenomics Based Individualized Chemotherapy,个体化疗,药物遗传学,（pharmacogenetics),药物基因组学,（pharmacognomics）,药物遗传学,：,研究与药物反应性/毒性相关的个体间DNA序列/,基因多态性,/,甲基化,的差异。,药物基因组学,：,将全基因组技术（即基因表达数据）用于预测一个患病个体对一个/一组药物的敏感性或抵抗性。,1.Microtubule-Associated Protein-,tau,is a Bifunctional Predictor of Endocrine Sensitivity and Chemotherapy Resistance in Estrogen Receptor Positive Breast Cancer,Clin Cancer Res 2007;13(7):2061-7,Tau,as predictor of response to preoperative paclitaxel/FAC chemotherapy in ER-positive breast cancer,low MAP-,tau,expression was associated with paclitaxel sensitivity.this association is particularly strong in ER positive breast cancer,Reduced,tau,expression in gastric cancer can identify candidates for successful Paclitaxel treatment,Br J Cancer 2006;94(12):1894-7,紫杉类,(paclitaxel，docetaxel),异长春花碱（VNB),CYP450,足叶乙甙（VP,16,),MDM2,开普拓（CPT,11,),WRN,Colorectal cancers treated with irinotecan,甲氨蝶呤（MTX,),DHFR,In vitro chemosensitivity of freshly explanted tumor cells to pemetrexed is correlated with target gene expression.,Invest New Drugs.2007 Oct;25(5):417-23,培美曲塞（Alimta,),DHFR,中国人群胃癌MTHFR 677C-T多态性分布：,CC 33.3%,CT 45.3%,TT 21.3%（5-FU敏感性较高）,5-氟尿嘧啶（5-FU）,MTHFR,中国人群STAT3 rs 4796793位点多态性分布：,CC 13.3%（IFNa敏感性较高）,CG 40.0%,GG 46.7%,干扰素（IFNa）,STAT3,碱基切除修复（base excision repair,BER）,DNA双链断裂修复,（DNA double strand break repair,DDSBR）,错配修复（mismatch repair,MMR）,核苷酸切除修复（nucleotide excision repair,NER）,铂类：,DNA修复途径,(DNA repair pathway）,):,XRCC1,核苷酸切除修复,ERCC1,ERCC1,(excision repair cross-Complementing 1),ERCC1 mRNA水平与铂类的敏感性密切相关，可以当成铂类化疗效果的独立预测指标。,BRCA1,(breast cancer 1),参与,DNA,修复，与铂类药物及作用于微管蛋白药物敏感性密切相关,XRCC1,(X-ray repair cross-complementing group 1),XRCC1,基因第399位密码子由,CGG CAG,的变异可以导致编码的氨基酸由,Arg Gln。,变异型的,DNA,修复能力提高，对铂类敏感性下降。,XPD,(xeroderma pigmentosum pomplementary group D),XPD,基因第751位密码子由,AAG CAG,的变异导致氨基酸由,Lys Gln。,变异型的表型导致,DNA,修复能力的提高，铂类敏感性下降。,GSTP1,(Glutathione-S-transferase P1),GSTP1,基因密码子105位缬氨酸,(Val),转变为异亮氨基酸,(Ile),，这一氨基酸的替换导致酶活性升高,铂类敏感性下降。,铂类药物疗效相关基因,(总结）,肺癌“个体化疗”,相关研究,美国临床研究回顾性,（,Massachusetts General Hospital）,(Dana-Farber/Harvard Cancer Center）,(多基因的SNP意义大 JCO 2004 22:2594）,*,美国临床研究回顾性,ERCC1 mRNA表达与NSCLC化疗（CDDPGEM）,疗效相关(J Clin Oncol 2002;22:2594),56例NSCLC（多中心）IIIb期（16例）、IV期（40例）,*,欧洲临床研究 前瞻性,（Spanish Lung Cancer Group）,ERCC1mRNA水平,（2005 ASCO 2007 JCO）,*,欧洲临床研究 前瞻性（,Spanish Lung Cancer Group）,（2005 ASCO 2007JCO）,生存时间：A组及B1,组根据ERCC1mRNA水平分为四组：,表达最低组的49pts中位生存期为,14,mo,表达最高组的8pts中位生存期为,8,mo,p=0.03,有效率：,BRCA1 mRNA,：,NSCLC（CDDPGEM）,Human Molecular Genetics,2004,MS:37.8 m,MS:12.7 m,MS:N.R,Stage,IV,NSCLC,（,tissue,）,Adeno,BAC,LCC,Others,EGFR,B,RCA1,mRNA,Mutated,Wild type,TKI,Erlotinib,Low Intermediate High,Gem/cis Doc or Nvb/cis Doc or Nvb,25%,25%,50%,20%,肺癌个体化治疗建议方案（2006 ASCO）,761病人,2006年9月,肺癌的术后辅助化疗：,只有,ERCC1（）者铂类化疗可获临床受益，,而ERCC1（）患者铂类化疗,没有价值,结果分析,小结,铂类ERCC1 mRNA临床III期前瞻性研究结果,XRCC1 SNP,BRCA1,紫杉类 bTublinIII,BRCA1,tau,VP-16 MDM2,MTX DHFR,Alimta DHFR,5-FU Ts、OPRT、DPD,CPT11 WRN,尚待解决的问题,1.临床研究：回顾性多 前瞻性少,2.基因选择：单一性多 组合性少,3.检查方法：DNASNP 甲基化,RNA定量技术,蛋白免疫组化,4.种族差异：不能照搬国外文献,5.实时个体化疗,消化系肿瘤“个体化疗”,相关研究,我们的初步探索,1.铂类相关基因SNPs与胃癌含铂化疗预后的关系,2.,ERCC1mRNA,水平与胃癌含铂化疗预后的关系,3.腹水上清,ERCC1和BRCA1mRNA,水平与顺铂敏感性,4.TET对胃癌化疗相关基因表达的调节作用,5.GA对胃癌Doc耐药的逆转作用,结语,“个体化治疗”是肿瘤精细化用药的必然选择，迄今已经,开始由laboratory research向clinical practice过渡。,1.铂类相关基因SNPs与胃癌含铂化疗预后的关系,Polymorphisms of XPD,GSTP1 and survival in gastric cancer patients,Polymorphisms of XRCC1 and survival in gastric cancer patients,Patients with G/G or G/A genotypes had significant better survival compared to patients with A/A genotype(P=0.030),For patients with ECOG PS,2,more obvious significant survival was shown between patients with or without G allele(,P,=0.002),结论（初步）,：,我国胃癌患者，XRCC1,399,SNP A/A基因型，含铂方案化疗生存时间远低于 G/G 或G/A基因型。,XPD,751,和 GSTP1,105,位点在我国胃癌人群，未见到差别。,Prognostic value of,ERCC1,mRNA expression levels,in advanced gastric cancer patients receiving 5-FU/oxaliplatin chemotherapy,Jia WeiBaorui Liu,Department of Oncology,Drum Tower Hospital Affiliated to Medical,School of Nanjing University&Clinical Cancer Institute of Nanjing University,Nanjing,China,2.ERCC1mRNA水平与胃癌含铂化疗预后的关系,Table 1 Clinical factors associated with overall survival,Characteristics,Patients,MST,a,(Months),P,(Log-rank test),No.,%,Age,years,57,36,47.4,15.7,0.943,57,40,52.6,10.7,Sex,Male,56,73.7,11.5,0.780,Female,20,26.3,11.7,ECOG PS,0-1,62,81.6,11.8,0.020,2,14,18.4,8.1,Initial staging,37,48.7,19.2,0.001,39,51.3,9.6,Grading,G2,20,26.3,10.7,0.972,G3,56,73.7,11.8,Site of tumor,Proximal stomach,28,36.8,9.8,0.45,Distal stomach,42,55.3,12.2,Whole stomach,6,7.9,11.3,No.of organs involved,b,0-1,49,64.5,16.9,0.004,2,27,35.5,7.6,a,MST:Median survival time.,b,No.of organs involved:number of organs(lymph nodes,liver,pancreas,peritoneum,lung,pleura)involved during the course of disease.,Table 2 ERCC1 and TS mRNA expression and survival,in gastric cancer patients,Factors,No.of patients,MST(Months)(95%CI),P,a,ERCC1 mRNA,Low,0.47,61,15.8(10.2-21.5),0.0001,High,0.47,15,6.2(4.6-7.9),TS mRNA,Low,6.06,21,10.1(5.4-18.9),0.01,High,6.06,55,12.2(3.7-16.4),a,Adjusted p value based on log-rank statistics after 1000 bootstrap simulations.,Table 3 Multivariate analysis on factors associated with overall survival,Factors,Relative risk(95%CI),P,ERCC1 mRNA,Low,0.47,1(,ref.),High,0.47,9.4(4.1-21.7),0.0001,Initial staging,1(,ref.),1.6(0.9-2.9),0.08,ECOG PS,0-1,1(,ref.),2,1.8(0.9-3.3),0.07,No.of organs involved,0-1,1(,ref.),2,1.9(1.1-3.3),0.03,Site of tumor,Whole stomach,1(,ref.),Proximal stomach,4.4(1.3-14.5),0.02,Distal stomach,3.8(1.1-16.6),0.04,Table 3 Multivariate analysis on factors associated with overall survival,结论（初步）：,我国胃癌患者，ERCC1,高表达者,，含铂方案化疗生存时间远低于 ERCC1,低表达者,。,3.腹水上清,ERCC1和BRCA1mRNA,水平与顺铂敏感性,图3-5：ERCC1 mRNA表达在未治胃肠肿瘤组与顺铂药物敏感的关系,图3-7：BRCA1 mRNA表达在胃肠肿瘤组与顺铂药物敏感的关系,4.TET对胃癌化疗相关基因表达的调节作用,control,TET,5-FU,5-FU,TET,Oxa,Oxa,TET,Doc,Doc,TET,判断标准：,CI1,at,Fa0.5,indicating,a,synergistic,effect,TET5-FU,TETOxa,TETDoc,结论：TET可以与Oxa等化疗发挥协同效应,为临床联合用药提供了依据,5.GA逆转胃癌对多希紫杉醇的耐药作用,Cancer Letters（accepted）,结论：GA可以逆转胃癌细胞Doc耐药性,为临床提供了依据,结语,“个体化治疗”是肿瘤精细化用药的必然选择，迄今已经,开始由laboratory research向clinical practice过渡。,