乳腺癌靶向治疗.ppt

《乳腺癌靶向治疗.ppt》由会员分享，可在线阅读，更多相关《乳腺癌靶向治疗.ppt（32页珍藏版）》请在优知文库上搜索。

1、lCurrent status and limitationlDrug resistance and principles to conquer2011StGallenInternationalExpertConsensuslEndocrine therapy One set of targeted therapies Neoadjuvant therapy, adjuvant therapy and metastatic disease Almost be weighted the same as chemotherapylLimited by relapse of disease and

2、development of resistance 50%HR-positiveprimarybreastcancerdonotrespondtofirst-lineendocrinetreatment(primaryresistance) Many of thesensitivepatients willeventuallyrelapsedespiteaninitialresponse(acquiredresistance)lCross-talk between ER and HER2lHER2overexpressionconfersintrinsicorprimaryresistance

3、toendocrinetherapylEndocrine therapy + Herceptin (phase III TAnDEM study)lEndocrine therapy + Lapatinib (anti-HER1/2 TKI)lCross-talk between downstream of ER/HER2lPI3K/Akt/mTORlPI3K inhibitors Wortmannin, LY294002 activity of these PI3K inhibitors has been observed poor solubility, instability and h

4、igh toxicitylAkt 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 insufficientlmTOR inhibitors Most highly investigated Rapamycin widely used as an im

5、munosuppressant in organ transplants poor solubility and instability limited the application on breast cancer therapylTemsirolimus (ToriselTM/CCI-779) approved by the FDA in 2007 for the intravenous treatment of metastatic renal cell carcinomaleverolimus (CerticanTM/RAD001) Promising results reporte

6、d in SABCS 2010 (Phase I study)lDefinitely Herceptin (trastuzumab)lmilestone 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

7、 secondary resistance within one or two yearslSignal transduction through other EGFR family memberslShares the same downstream of signallPertuzumab monoclonalantibodyagainstthedimerizationdomainIIofHER2 requiredforligand-dependentdimerizationwithHER3 Trastuzumab + Pertuzumab: clinical benefit rate 5

8、0%lClinical trails underwaylCLEOPATRAlNEOSPHERElcleavage of HER-2 extracellular domain to form the truncated HER-2 receptorlLapatinib Dual TKI (EGFR and HER2) Blocks the intercellular kinase receptors Penetrate the blood-brain barrier Low cardiotoxicity (1.6% Vs 11%)lapproved by the FDA in 2007 for

9、the treatment of patients with advanced or metastatic breast cancerlClinical trails underwaylTEACHlALTTOlNeoALTTOlaberrantactivationofsignallingpathwaysdownstreamofthereceptor activatingPI3KmutationslTrastuzumab + Everolimus (mTOR inhibitor)lPhase Ib studylPositive resultslTrastuzumab-DM1 (T-DM1) HE

10、R-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 mechanismslPoor prognosislNo treatment beside chemotherapylChemotherapy resistance i

11、n one or two yearslNew hope largemajorityofbreastcancerswithBRCA1mutationshavethetriple-negativephenotypeandalsoclusteramongthebasal-likegrouplBRCA1 plays an important role in the repair of DNA double strand breaks (DSBs)lBRCA1 mutation results in a dysfunction of homologous recombination (HR) repai

12、rlpoly-ADP-ribose polymerase-1 (PARP-1) plays a major role in response to extensive DNA damage in single strand breaks (SSBs) repairInhibition of PARP-1SSBsDSBsdysfunction of HR repairlPARP inhibitors Olaparib (AZD2281) BSI-201 AG014699 ABT-888lPhase I studylEGFR (HER1) 50% overexpression in TNBCs P

13、otential target Cetuximab (monoclonal antibody of EGFR) Limited activity Gefitinib (EGFR TKI) Disappointing resultsBreast cancerLuminal A/BHER2 overexpressionBasal-likeEndocrine therapyHR+ HER2-HR+ HER2+Endocrine therapy + HerceptinHR+ mTOR+Endocrine therapy + mTOR inhibitorHER2+ HER3+HER2 cleavedHER2+ mTOR+PertuzumabLapatinibHerceptin + mTOR inhibitorBRCA mutationEGFR+PARP inhibitorEGFR inhibitorlThanks for listening