乳腺癌靶向治疗34张课件

,单击此处编辑母版标题样式,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,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,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,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,乳腺癌靶向治疗,1、战鼓一响，法律无声。英国,2、任何法律的根本；不，不成文法本身就是讲道理法律，也-即明示道理。爱科克,3、法律是最保险的头盔。爱科克,4、一个国家如果纲纪不正，其国风一定颓败。塞内加,5、法律不能使人人平等，但是在法律面前人人是平等的。波洛克,乳腺癌靶向治疗乳腺癌靶向治疗1、战鼓一响，法律无声。英国,2、任何法律的根本；不，不成文法本身就是讲道理法律，也-即明示道理。爱科克,3、法律是最保险的头盔。爱科克,4、一个国家如果纲纪不正，其国风一定颓败。塞内加,5、法律不能使人人平等，但是在法律面前人人是平等的。波洛克Targeted therapies for breast cancertowards individualized therapyFocusesCurrent status and limitation,Drug resistance and principles to conquer,Limited by relapse of disease and development of resistance,50%HR-positiveprimarybreastcancerdonotrespondtofirst-lineendocrinetreatment(primaryresistance),Many of thesensitivepatients willeventuallyrelapsedespiteaninitialresponse(acquiredresistance),Mechanism 1,Cross-talk between ER and HER2,HER2overexpressionconfersintrinsicorprimaryresistancetoendocrinetherapy,Endocrine therapy+Herceptin(phase III TAnDEM study),Endocrine therapy+Lapatinib(anti-HER1/2 TKI),Mechanism 2,Cross-talk between downstream of ER/HER2,PI3K/Akt/mTOR,PI3K inhibitors,Wortmannin,LY294002,activity of these PI3K inhibitors has been observed,poor solubility,instability and high toxicity,Akt inhibitors,Perifosine,synthetic inhibitor which can prevent Akt recruitment to the membrane and block activation of downstream effectors,good tolerance,objective response rates are disappointing and insufficient,mTOR inhibitors,Most highly investigated,Rapamycin,widely used as an immunosuppressant in organ transplants,poor solubility and instability limited the application on breast cancer therapy,Temsirolimus(Torisel,TM,/CCI-779),approved by the FDA in 2007 for the intravenous treatment of metastatic renal cell carcinoma,everolimus(Certican,TM,/RAD001),Promising results reported in SABCS 2010(Phase I study),HER2 overexpression breast cancer,Definitely Herceptin(trastuzumab),milestone in the therapy of HER-2 positive breast cancer with attractive clinical benefits,approximately 70%of patients may have primary resistance to trastuzumab,the majority of patients who achieve initial efficacy tend to develop secondary resistance within one or two years,Mechanism 1,Signal transduction through other EGFR family members,Shares the same downstream of signal,Pertuzumab,monoclonalantibodyagainstthedimerizationdomainIIofHER2,requiredforligand-dependentdimerizationwithHER3,Trastuzumab+Pertuzumab:clinical benefit rate 50%,Clinical trails underway,CLEOPATRA,NEOSPHERE,Mechanism 2,cleavage of HER-2 extracellular domain to form the truncated HER-2 receptor,Lapatinib,Dual TKI(EGFR and HER2),Blocks the intercellular kinase receptors,Penetrate the blood-brain barrier,Low cardiotoxicity(1.6%Vs 11%),approved by the FDA in 2007 for the treatment of patients with advanced or metastatic breast cancer,Clinical trails underway,TEACH,ALTTO,NeoALTTO,Mechanism 3,aberrantactivationofsignallingpathwaysdownstreamofthereceptor,activatingPI3Kmutations,Trastuzumab+Everolimus(mTOR inhibitor),Phase Ib study,Positive results,One more thing,Trastuzumab-DM1(T-DM1),HER-2 monoclonal antibody conjugated with a fungal toxin DM1(maytansine),Maytansine is an antimicrotubule agent that inhibits the assembly of cellular microtubules,successfully overcome several trastuzumab resistance mechanisms,Basal-like breast cancer(,TNBC),Poor prognosis,No treatment beside chemotherapy,Chemotherapy resistance in one or two years,New hope,largemajorityofbreastcancerswithBRCA1mutationshavethetriple-negativephenotypeandalsoclusteramongthebasal-likegroup,BRCA1 plays an important role in the repair of DNA double strand breaks(DSBs),BRCA1 mutation results in a dysfunction of homologous recombination(HR)repair,poly-ADP-ribose polymerase-1(PARP-1)plays a major role in response to extensive DNA damage in single strand breaks(SSBs)repair,Inhibition of PARP-1,SSBs,DSBs,dysfunction of HR repair,PARP inhibitors,Olaparib(AZD2281),BSI-201,AG014699,ABT-888,Phase I study,EGFR(HER1),50%overexpression in TNBCs,Potential target,Cetuximab(monoclonal antibody of EGFR),Limited activity,Gefitinib(EGFR TKI),Disappointing results,Breast cancer,Luminal A/B,HER2 overexpression,Basal-like,Endocrine therapy,HR+HER2-,HR+HER2+,Endocrine therapy,+Herceptin,HR+mTOR+,Endocrine therapy,+mTOR inhibitor,HER2+HER3+,HER2 cleaved,HER2+mTOR+,Pertuzumab,Lapatinib,Herceptin+mTOR inhibitor,BRCA mutation,EGFR+,PARP inhibitor,EGFR inhibitor,Thanks for listening,56,、书不仅是生活，而且是现在、过去和未来文化生活的源泉。,库法耶夫,57,、生命不可能有两次，但许多人连一次也不善于度过。,吕凯特,58,、问渠哪得清如许，为有源头活水来。,朱熹,59,、我的努力求学没有得到别的好处，只不过是愈来愈发觉自己的无知。,笛卡儿,60,、生活的道路一旦选定，就要勇敢地走到底，决不回头。,左,拉,