乳腺癌治疗内分泌耐药机制优质课件

,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,3/2/2015,乳腺癌治疗内分泌耐药机制,临床医师面临的内分泌治疗耐药的挑战,乐观结局：,约,70%BC,激素受体阳性，可从内分泌治疗中获益：,Tamoxifen,、,Ais,、,Fulvestrant,面临挑战：,大约,30%,原发内分泌治疗耐药，有效者中,30%,0,年继发耐药,内分泌治疗耐药机理未完全明确,破解之道：,针对内分泌治疗耐药的不同机理，新药已进入临床试验或获批进入临床,识别适合选用这些新药的亚组人群,2,一、内分泌“耐药”的患者比例调查,3,1,、早期乳腺癌（,M0,）内分泌治疗后十年进展率超过三分之一,随访年限,随访满足随访年限的患者总例数,疾病进展率,死亡率,内分泌治疗后三年,2510,7.00%,3.90%,内分泌治疗后五年,1536,12.60%,9.10%,内分泌治疗后十年,538,35.70%,30.90%,华西医院,1989-,今,早期乳腺癌,接受内分泌治疗共,4676,例，其中,4,随访年限,随访满足随访年限的患者总例数,疾病进展率,死亡率,内分泌治疗后三年,35,31.40%,20.00%,内分泌治疗后五年,23,65.20%,39.10%,内分泌治疗后十年,15,80.00%,73.30%,华西医院,1989-,今,转移性乳腺癌,接受内分泌治疗共,91,例，其中,2,、转移性乳腺癌（,M1,）内分泌治疗三年后进展率,即超过三分之一,5,二、内分泌治疗可能耐药机制,6,内分泌治疗可能耐药机制,一、,ER,的改变,ER,表达水平下降，突变或磷酸化,二、,RTKs,（,receptor tyrosine kinases,）及其下游通路的激活,跨膜酪氨酸激酶受体,通路表皮生长因子,受体,(EGFR,),、胰岛素样生长因子,受体,(IGFR,),、成纤维细胞生长因子,受体,(FGFR,),、人,表皮生长因子受体,2(HER2),第二信使,(,细胞内,),PI3K/AKT/mTOR,通路、,Ras-Raf-MEK-MAPK,通路,三、,细胞周期正调控分子活化或上调（,cyclin D1,cyclin E,Myc,）,细胞周期负调控分子失活或下调（,p21,，,p27,）,四、,抗凋亡因子活化或上调（,BCL-XL,）,促凋亡因子失活或下调（,BCL2-interacting killer,，,caspase 9,）,7,The Breast 20(2011)S3,S42S49,ER signaling and cross talk with RTKs,Cytoplasma,nucleus,Estrogen,ER,ER,ERE,ER target gene transcription,RTKs:EGFR/HER2/,IGFR/FGFR,Growth factor,P85,P110,PI3K,AKT,mTOR,PTEN,RAS,MAPK,Proliferation,Survival,Invasion,Protein,sythesis,8,Anti-Estrogen therapy leads to RTKs activation,Cytoplasma,nucleus,Estrogen,ER,ER,ERE,ER target gene transcription,RTKs:EGFR/HER2/,IGFR/FGFR,Growth factor,P85,P110,PI3K,AKT,mTOR,PTEN,RAS,MAPK,Proliferation,Survival,Invasion,Protein,sythesis,AI,TAM,9,三、内分泌治疗 耐药的主要临床对策,10,临床对策概括（一）,1,、联合抑制,ER,通路与,RTKs,下游通路,Inhibitors of PI3K,Akt,and/or mTOR pathway(everolimus,）,Inhibitors of Ras-Raf-MEK-MAPK pathway,(MEK inhibitor AZD6244,）,AMPK activator,（,metformin,AMPK,是,mTOR,的负调控分子,),2,、联合抑制,ER,通路与,RTKs,及其生长因子,IGF1 or IGF1R neutralizing antibodies(AMG-479,）,HER-2 blocking therapy(trastuzumab,）,EGFR inhibitors,FGFR inhibitors,11,临床对策,概括（二）,3,、阻滞细胞周期进程,Cyclin D1/cyclin E inhibitor,（,PD0332991,）,4,、加强对,ER,的抑制作用,（,1,）抑制,ER,去乙酰化活化,组蛋白去乙酰化酶,HDAC inhibitors(vorinostat),（,2,）抑制,ER,的磷酸化,Src inhibitors(dasatinib,）,12,1,、,PI3K-Akt-mTOR,（,PAM,）通路抑制剂,临床研究进展,13,（,1,）,PI3K inhibitors,Generic name,Company,Stage of development,Target,PI3K inhibitors,Pan-PI3K inhibitors,XL-147/EXEL6147,Exelixis/Sanofi-Aventis,BC,II,Class I PI3K/EGFR inhibitor,PX866,Oncot hyreon,II,PI3K inhibitor,BKM120,Novartis,BC,III,PI3K inhibitor,RG7321/GDC0941,Roche,BC,I,PI3K inhibitor,BAY806946,Bayer Schering Pharma,I,PI3K inhibitor,GSK2126458,GlaxoSmithkline,I,PI3K inhibitor,CH5132799,Roche,I,PI3K inhibitor,ATU027,Silence Therapeutics,I,PKN3 inhibitor(RNA interferen agent),PI3K isoform-specific inhibitors,CAL101,Calistoga Pharmaceuticals,II,PI3K delta inhibitor,BYL719,Novartis,I,PI3K alpha inhibitor,GSK2636771,GlaxoSmithkline,I/II,PI3K beta inhibitor,Chin J Cancer;2013;Vol.32 Issue 5,14,（,2,）,AKT inhibitors,Generic name,Company,Stage of development,Target,AKT inhibitors,Allosteric AKT inhibitors,MK-2206,Merck,BC,II,AKT inhibitors,GSK690693,GlaxoSmithkline,I,AKT inhibitor,RX0201(Archexin),Rexahn Pharmaceuticals,II,AKT Ant i sense,ATP-competitive AKT inhibitors,Triciribine phosphate,VioQuest Pharmaceuticals /Cahaba Pharmaceuticals,BC,II,AKT inhibitor,PBI-05204(oleandrin),Phoenix Biosciences,I,AKT,FGF-2,NF-kappa B,GSK2110183,GlaxoSmithkline,I,AKT inhibitor,GSK2141795,GlaxoSmithkline,I,AKT inhibitor,RG7440,Roche,I,AKT inhibitor,GDC0068,Array Biopharma,I,AKT inhibitor,AKT inhibitor,Pan-AKT inhibitor,AZD5363,Astra Zeneca,I,Pan-AKT inhibitor,15,（,3,）,mTOR inhibitors,Generic name,Company,Stage of development,Target,mTOR inhibitors,Rapalog mTOR inhibitors,Everolimus(,Afinitor),Novartis,BC,RCC,Launched,mTOR inhibitor,Temsirolimus(,TORISEL),Pfizer,RCC Launched/,BC discontinued,mTOR inhibitor,ridaforolimus,ARIAD Pharmaceuticals/Merck,Sarcoma III/,BC,I,mTOR inhibitor,sirolimus,Celgene,I,mTOR inhibitor,mTORC1/2,inhibitors,OSI027,Astellas Pharma,I,mTORC1/2 inhibitors,AZD8055,AstraZeneca,II,mTORC1/2 inhibitors,AZD2014,AstraZeneca,I,mTORC1/2 inhibitors,INK128,Intellikine,I,mTORC1/2 inhibitors,CC223,Celgene,II,mTORC1/2 inhibitors,Most advanced,16,（,4,）,Dual PI3K-mTOR inhibitors,Generic name,Company,Stage of development,Target,Dual PI3K-mTOR inhibitors,BEZ235,Novartis,BC,I,PI3K-mTOR inhibitor,SAR245409/XL765,Exelixis/Sanofi-Aventis,BC,II,PI3K-mTOR inhibitor,SF1126,Semafore Pharmaceuticals,I,PI3K-mTOR inhibitor,RG7422,Roche/Piramal,I,PI3K-mTOR inhibitor,PF05212384,Pfizer,I,PI3K-mTOR inhibitor,PF4691502,Pfizer,I,PI3K-mTOR inhibitor,PP-242,I,PI3K-mTOR inhibitor,17,多个适应症,药理作用,既往接受舒尼替尼或索拉非尼治疗失败的晚期肾细胞癌,神经内分泌肿瘤,室管膜下巨细胞星状细胞瘤,肾血管平滑肌脂肪瘤,非甾体类,AI,治疗失败,的,进,展期激素受体,阳性,乳腺癌,Everolimus,的药理作用及多个适应症,依维莫司可与胞内蛋白,FKBP12,结合形成抑制性的复合体,mTORC1,，该复合体可抑制,mTOR,的活性，从而导致转录调节因子,S6K1,和真核生物延伸因子,4E-BP,的活性降低，从而干扰细胞周期、血管新生、糖酵解等相关蛋白的翻译和合成。,依维莫司是肿瘤细胞、内皮细胞、成纤维细胞、血管平滑肌细胞生长和增殖的强效抑制剂，并可在体内外抑制实体瘤的糖酵解。,18,BOLERO-2,依西美坦,依维莫司,治疗,HR+HER2-,晚期乳腺癌患者,III,期临床试验,2013,年研究结果,19,TAMRAD,他莫西芬,依维莫司治疗,HR+