肿瘤分子靶向治疗的思考

BATTLE PROGRAMlBiomarker-based Approach of Targeted Therapy for Lung Cancer Elimination.Waun Ki Hong et allBiomarker Analysis in Core Biopsy Select Adequate Target Therapy未来的方向l加强癌症基因分型及药物基因学研究，寻找各种靶向治疗药物的适用或预测指标。lTreating tumors according to their molecular defects and their upgraded or downgraded signal transduction pathways.Clinical Predictors of Gefitinib or Erlotinib Efficacy in NSCLClNever smoker lFemale gender lAdenocarcinomalBronchoalveolar adenocarcinoma lAsian origin肿瘤分子靶向治疗的思考中山大学肿瘤防治所管忠震分子靶向治疗研究的兴起l上世纪70-80年代，癌症生物学研究迅速发展，从分子水平了解肿瘤发生、发展的机制。lScientific research has increasingly identified key genetic events critical to specefic cancer development.Targeting TherapylA new generation of small molecules or MABs that rationaly designde to inhibit specific signal transduction or transcription pathways that are critical for cancer cell growth and survival.EGFR Blockade as Cancer therapylThe EGFR autocrine pathways plays an important role in the development and progression of human epithelial cancer.lEGFR activation triggers a cascade of signals leading to cell proliferation,production of antiogenic factors and promotion of invasion and metastasis.lHigh expression of EGFR is common in a wide variety of human cancers and is generally associated with advanced disease and poor prognosis,and with resistance to hormone therapy,chemotherapy,or radiotherapy.EGFR EGFR Blockade Blockade as as Cancer Cancer Therapy:Therapy:J.J.mendelsohnmendelsohns Hypothesis(Early 1980s)s Hypothesis(Early 1980s)lThe blockade of EGFR activation may inhibit cancr cell proliferation.lCancer cells may be selectively sensitive to EGFR inhibition as compared to normal cells.lSelective anti-EGFR agents may be developed.靶向治疗研究已获得明显成果GleevecNorvatis CML,GISTGefitinibAstraZenicaNSCLCErlotinibGenetech,Roche NSCLCErbituxImClone,MerchCRC,H/NHerceptinGenetech,Roche BreastBevacezumab RocheCRC,lungSorafenibBayer RCCSunitinibPfeizerRCC,GIST许多新的分子靶向药物仍在开发研究中ZD6474(Vandetanib)AZlung GW786034(Pazopanib)GSKRCCCA163048(lxabepilone)BMSBreastEGF10453(Lapatinib)GSKBreastEnzastaurinEil-lillyGBM,NHLDasatinib耐药CMLPF3512676Pfeizer lung靶向治疗药物取得的成功若干化疗无效（失败）的病例取得明显疗效Iressa,Tarceva NSCLC Pt based chemo FailureSorafenib,Sunibinib RCC,Refractory GISTGleevec CML,GISTHerceptin Her2(+)Breast CaErbitux Chemo-resistant CRCErlotinib Pancreas Ca靶向治疗药物取得的成功并用化疗（放疗），提高疗效Erbitux Irinotecan,FOLFOX,5FU/LV(CRC)Avastin IFL(CRC),Carbo/Taxol(NSCLC)Herceptin Taxanes,NVB,Xeloda(Breast)Rituxinab CHOP/R-CHOP(NHL)靶向治疗药物取得的成功选择性作用于肿瘤细胞？相对较低毒性，特别是血液毒性 不易达到MTD，治疗剂量不需接近MTD “即使无效，也不至于造成明显伤害”？Iressa 治疗指数提高（Thomas G Roberts,MGH）靶向治疗药物存在的问题l（1）整体效率不高 IRESSA IDEAL1 RR 18.4%(n=209)IDEAL2 RR 11.8%(n=216)TARCEVA phase RR 15.8%(n=57)TARCEVA BR21 RR 9%(n=488)IRESSA ISEL RR 6.5%(非亚)(n=1305)RR 12.0%(亚)(n=342)全组：无Survival Benefit只有10%左右病人取得客观反应靶向治疗药物存在的问题(2)有效期不长 需持续不断用药，停药复发进展 Gleevec for CML通常有效期较长，停药复发 for GIST，一般10-14个月后失效 肿瘤细胞基因突变 信号传导旁路 不再受抑制 所有靶向药物 缓解时间有限 靶向治疗药物存在的问题（3）价格昂贵 临床前及临床开发研究成本高昂 IRESSA TARCEVA HERCEPTIN ERBITUX AVASTIN 每月2-10万靶向治疗药物存在的问题（4）毒性.靶向药物不可能完全选择性作用于肿瘤细胞.生长因子受体、蛋白激酶，信号传递通道具有正常功能 皮疹，甲沟炎，腹泻，心力衰竭，神经症状，肾衰，ILD出血，胃肠穿孔，高血压，血栓栓塞，蛋白尿等.需要时间积累资料，确定其安全性解决靶向治疗药物抗药性的可能办法多种靶向治疗药物共用Bundling，以便阻断多种信号传递通道问题:（1）COST （2）Toxicity问题的症结Oncologist的习惯性思维:Disease(Anatomy)Orientede.g Breast Ca:Anthracyclines,Taxes Lung Ca:Pt based doublets Lymphomas:CHOPlikes regimes Colorectal:5Fu based,Campto,Oxaliplatin etc Dis Oriented Therapy的缺陷l每一种肿瘤常为Molecularly Heterogeneousl不可能选用一种靶向药物治疗某一肿瘤的全部lBreast Ca,Estrogen Receptor(+),可用内分泌治疗lHer2 Over expression Ampilcation 者可能Herceptin治疗l大部分肿瘤的分子学分型仍不健全或空白l分子靶向治疗超前于分子分型诊断In the future，tumor will be thought of and grouped together based on their common genetic defects rather than anatomic tumor site.EGFR Gene Mutations in NSCLClSomatic EGFR gene mutations are present in a small(10%)but defined subset of NSCLC patients.lEGFR gene mutations are approximately three-fold more frequent in the Asian population.lEGFR gene mutations are generally clustered in the tyrosine kinase domain(within exons 18-24).lEGFR gene mutations are associated with increased sensitivity to small molecule EGFR-TK inhibitors,such as gefitinib and erlotinib.lHowever,EGFR gene mutations are not functionally and clinically equal to cach other.EGFR gene mutations which confer resistance to EGFR-TK inhibitors have been identified.lEGFR gene mutations are generally more frequent in adenocarcinoma from”never smokers”,in Japanese and in female patients.We should limit the use of our drugs to those who are really going to benefit from them.