腫瘤分子靶向治療的思考

1、腫瘤分子靶向治療的思考l加強癌癥基因分型及藥物基因?qū)W研究，尋找各種靶向治療藥物的適用或預(yù)測指標(biāo)。lTreating tumors according to their molecular defects and their upgraded or downgraded signal transduction pathways.lNever smoker lFemale gender lAdenocarcinomalBronchoalveolar adenocarcinoma lAsian origin中山大學(xué)腫瘤防治所管忠震l上世紀(jì)70-80年代，癌癥生物學(xué)研究迅速發(fā)展，從分子水平了解腫瘤發(fā)生

2、、發(fā)展的機制。lScientific research has increasingly identified key genetic events critical to specefic cancer development.lA 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 survi

3、val.lThe 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 co

4、mmon 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. lThe blockade of EGFR activation may inhibit cancr cell proliferation.lCancer cells may be selectively sensitive to EGFR i

5、nhibition as compared to normal cells.lSelective anti-EGFR agents may be developed.GleevecNorvatis CML,GISTGefitinibAstraZenicaNSCLCErlotinibGenetech,Roche NSCLCErbituxImClone,MerchCRC,H/NHerceptinGenetech,Roche BreastBevacezumab RocheCRC,lungSorafenibBayer RCCSunitinibPfeizerRCC,GISTZD6474(Vandetan

6、ib)AZlung GW786034(Pazopanib) GSKRCCCA163048(lxabepilone) BMSBreastEGF10453(Lapatinib)GSKBreastEnzastaurinEil-lillyGBM,NHLDasatinib耐藥CMLPF3512676Pfeizer lung若干化療無效（失敗）的病例取得明顯療效Iressa,Tarceva NSCLC Pt based chemo FailureSorafenib,Sunibinib RCC,Refractory GISTGleevec CML,GISTHerceptin Her2(+) Breast C

7、aErbitux Chemo-resistant CRCErlotinib Pancreas Ca并用化療（放療），提高療效Erbitux Irinotecan,FOLFOX,5FU/LV(CRC)Avastin IFL(CRC) ,Carbo/Taxol(NSCLC)Herceptin Taxanes,NVB,Xeloda(Breast)Rituxinab CHOP/R-CHOP(NHL)選擇性作用于腫瘤細(xì)胞？ 相對較低毒性，特別是血液毒性 不易達(dá)到MTD，治療劑量不需接近MTD “即使無效，也不至于造成明顯傷害”？Iressa 治療指數(shù)提高（Thomas G Roberts,MGH）l（1

8、）整體效率不高 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%(非亞)(n=1305) RR 12.0%(亞)(n=342) 全組：無Survival Benefit只有10%左右病人取得客觀反應(yīng)(2)有效期不長 需持續(xù)不斷用藥，停藥復(fù)發(fā)進(jìn)展 Gleevec for CML通常有效期較長，停藥復(fù)發(fā) for GIST，一般10-14個月后失效 腫瘤細(xì)胞基因突變 信號傳導(dǎo)旁路 不再受抑制 所有

9、靶向藥物 緩解時間有限 （3）價格昂貴 臨床前及臨床開發(fā)研究成本高昂 IRESSA TARCEVA HERCEPTIN ERBITUX AVASTIN 每月2-10萬（4）毒性.靶向藥物不可能完全選擇性作用于腫瘤細(xì)胞.生長因子受體、蛋白激酶，信號傳遞通道具有正常功能 皮疹，甲溝炎，腹瀉，心力衰竭，神經(jīng)癥狀，腎衰，ILD出血，胃腸穿孔，高血壓，血栓栓塞，蛋白尿等.需要時間積累資料，確定其安全性多種靶向治療藥物共用Bundling，以便阻斷多種信號傳遞通道問題:（1）COST （2）ToxicityOncologist的習(xí)慣性思維:Disease(Anatomy) Orientede.g Brea

10、st Ca:Anthracyclines,Taxes Lung Ca:Pt based doublets Lymphomas:CHOPlikes regimes Colorectal:5Fu based,Campto,Oxaliplatin etcl每一種腫瘤常為Molecularly Heterogeneousl不可能選用一種靶向藥物治療某一腫瘤的全部lBreast Ca,Estrogen Receptor(+),可用內(nèi)分泌治療lHer2 Over expression Ampilcation 者可能Herceptin治療l大部分腫瘤的分子學(xué)分型仍不健全或空白l分子靶向治療超前于分子分型診斷

11、In the future，tumor will be thought of and grouped together based on their common genetic defects rather than anatomic tumor site.lSomatic 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

12、 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 mutation