恶性肿瘤的个体化治疗 (1)课件

1、“标准化疗”的成就与无奈：当今肿瘤的化疗： 胃癌：FAM FAMtx EAP FP ECF FOLFOX TFP RR: 28%-46% 均50% 肺癌：RR30-40%肿瘤“异质性”：有效率毒副作用-个体差异很大个体化疗： 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20062007 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/Pharma

2、cogenomics 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。DPD: 二氢嘧啶脱氢酶 TS: 胸腺嘧啶核苷酸合成酶 OPRT:乳清酸磷酸核糖基转移酶 TP:胸(腺嘧啶脱氧核)苷磷酸化酶氟脲密啶 (5-FU)1. Microtubule-Associated Protein-tau is

3、a Bifunctional Predictor of Endocrine Sensitivity and Chemotherapy Resistance in Estrogen Receptor Positive Breast Cancer Clin Cancer Res 2007;13(7):2061-7Tau as predictor of response to preoperative paclitaxel/FAC chemotherapy in ER-positive breast cancerlow MAP-tau expression was associated with p

4、aclitaxel sensitivity. this association is particularly strong in ER positive breast cancerReduced 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（VP16) MDM2开普拓（CPT11) WRN甲氨蝶呤（

5、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

6、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ERCC1ERCC1(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

7、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

8、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 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）BRCA1 mRNA ： NSCLC （CDDPGEM） Human Molecular Genetics, 2

9、004MS: 37.8 mMS: 12.7 mMS: N.RStage IV NSCLC（tissue） Adeno, BAC, LCCOthersEGFRBRCA1 mRNAMutatedWild typeTKIErlotinibLow Intermediate HighGem/cis Doc or Nvb/cis Doc or Nvb25%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 XRC

10、C1 SNP BRCA1紫杉类 bTublinIII BRCA1 tauVP-16 MDM2MTX DHFRAlimta DHFR5-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

11、. 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 patientsPolymorphisms of XRCC1 and survival in gastric cancer patientsPatients with G/G or G/A genotypes

12、 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，XRCC1399 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。 XPD751和 GSTP1105位点在我国胃癌人群，未见到差别

13、。 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,

14、China2. ERCC1mRNA水平与胃癌含铂化疗预后的关系Table 1 Clinical factors associated with overall survivalCharacteristicsPatientsMST a(Months)P(Log-rank test)No.%Age, years573647.415.70.943574052.610.7SexMale5673.711.50.780Female2026.311.7ECOG PS0-16281.611.80.02021418.48.1Initial staging3748.719.2 0.0013951.39.6Grad

15、ingG22026.310.70.972G35673.711.8Site of tumorProximal stomach2836.89.80.45Distal stomach4255.312.2Whole stomach67.911.3No.of organs involved b0-14964.516.90.00422735.57.6a MST: Median survival time.b No.of organs involved: number of organs (lymph nodes, liver, pancreas, peritoneum, lung, pleura) inv

16、olved during the course of disease. Table 2 ERCC1 and TS mRNA expression and survival in gastric cancer patientsFactorsNo. of patientsMST (Months) (95% CI)PaERCC1 mRNALow, 0.476115.8 (10.2-21.5) 0.0001High, 0.47156.2 (4.6-7.9)TS mRNALow, 6.062110.1 (5.4-18.9)0.01High, 6.065512.2 (3.7-16.4)a Adjusted

17、 p value based on log-rank statistics after 1000 bootstrap simulations.Table 3 Multivariate analysis on factors associated with overall survivalFactorsRelative risk (95% CI)PERCC1 mRNALow, 0.471 (ref.)High, 0.479.4 (4.1-21.7)0.0001Initial staging1 (ref.)1.6 (0.9-2.9)0.08ECOG PS0-11 (ref.)2 1.8 (0.9-

18、3.3)0.07No.of organs involved0-11 (ref.)21.9 (1.1-3.3)0.03Site of tumorWhole stomach1 (ref.)Proximal stomach4.4 (1.3-14.5)0.02Distal stomach3.8 (1.1-16.6)0.04Table 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