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1、Targeted therapies for breast cancertowards individualized therapy,Focuses,Current status and limitationDrug resistance and principles to conquer,Intrinsic subtypes of breast cancer,2011 St Gallen InternationalExpert Consensus,HR-positive breast cancer(luminal A,B),Endocrine therapyOne set of target
2、ed therapiesNeoadjuvant therapy,adjuvant therapy and metastatic diseaseAlmost be weighted the same as chemotherapy,Limited by relapse of disease and development of resistance50%HR-positiveprimarybreastcancerdonotrespondtofirst-lineendocrinetreatment(primaryresistance)Many of thesensitivepatients wil
3、leventuallyrelapsedespiteaninitialresponse(acquiredresistance),Mechanism 1,Cross-talk between ER and HER2HER2overexpressionconfersintrinsicorprimaryresistancetoendocrinetherapy,Endocrine therapy+Herceptin(phase III TAnDEM study)Endocrine therapy+Lapatinib(anti-HER1/2 TKI),Mechanism 2,Cross-talk betw
4、een downstream of ER/HER2PI3K/Akt/mTOR,PI3K inhibitorsWortmannin,LY294002activity of these PI3K inhibitors has been observedpoor solubility,instability and high toxicity,Akt inhibitorsPerifosinesynthetic inhibitor which can prevent Akt recruitment to the membrane and block activation of downstream e
5、ffectorsgood toleranceobjective response rates are disappointing and insufficient,mTOR inhibitorsMost highly investigatedRapamycinwidely used as an immunosuppressant in organ transplantspoor solubility and instability limited the application on breast cancer therapy,Temsirolimus(ToriselTM/CCI-779)ap
6、proved by the FDA in 2007 for the intravenous treatment of metastatic renal cell carcinomaeverolimus(CerticanTM/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 w
7、ith attractive clinical benefitsapproximately 70%of patients may have primary resistance to trastuzumabthe 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 membersShares the same d
8、ownstream of signal,PertuzumabmonoclonalantibodyagainstthedimerizationdomainIIofHER2requiredforligand-dependentdimerizationwithHER3Trastuzumab+Pertuzumab:clinical benefit rate 50%,Clinical trails underwayCLEOPATRANEOSPHERE,Mechanism 2,cleavage of HER-2 extracellular domain to form the truncated HER-
9、2 receptor,LapatinibDual TKI(EGFR and HER2)Blocks the intercellular kinase receptorsPenetrate the blood-brain barrierLow cardiotoxicity(1.6%Vs 11%)approved by the FDA in 2007 for the treatment of patients with advanced or metastatic breast cancer,Clinical trails underwayTEACHALTTONeoALTTO,Mechanism
10、3,aberrantactivationofsignallingpathwaysdownstreamofthereceptoractivatingPI3Kmutations,Trastuzumab+Everolimus(mTOR inhibitor)Phase Ib studyPositive results,One more thing,Trastuzumab-DM1(T-DM1)HER-2 monoclonal antibody conjugated with a fungal toxin DM1(maytansine)Maytansine is an antimicrotubule ag
11、ent that inhibits the assembly of cellular microtubulessuccessfully overcome several trastuzumab resistance mechanisms,Basal-like breast cancer(TNBC),Poor prognosisNo treatment beside chemotherapyChemotherapy resistance in one or two years,New hopelargemajorityofbreastcancerswithBRCA1mutationshaveth
12、etriple-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 DN
13、A damage in single strand breaks(SSBs)repairInhibition of PARP-1SSBsDSBs,dysfunction of HR repair,PARP inhibitorsOlaparib(AZD2281)BSI-201AG014699ABT-888Phase I study,EGFR(HER1)50%overexpression in TNBCsPotential targetCetuximab(monoclonal antibody of EGFR)Limited activityGefitinib(EGFR TKI)Disappointing results,Thanks for listening,
