VHL综合征与肾癌靶向治疗

VHL综合征与肾癌靶向治疗ASTORYOFVHLDISEASEAstoryfromVHLallianceRush,18,wentforaneyetestaftercomplainingofvisualdisturbances。ShewasdiagnosedwithVHLdisease-araregeneticillnesswhichcausestumorstogrowinvariouspartsofthebody.VHLDiseasevonHippel-LindauDiseaseThesegrowthsaremadeofnewlyformedbloodvesselsandalthoughtheyaretypicallybenign,theycancauseseriousorlife-threateningcomplications,butVHLtumorsinthekidneyandpancreascangrowtoastagewheretheybecomemalignantandcanspreadtootherpartsofthebody.RCCdevelopsinabout50%

ofpatientswithVHLdiseaseandisdistinctiveforearlyageatonsetandbilateralandmultifocalinvolvement

RCChasnowbecomethemostcommoncauseofmortalityinpatientswithVHLdisease.VHLDiseaseArealcase女性、45岁

因“突发呕血1月余”入院

1月前晚饭后无明显诱因出现呕血，鲜红色，量约200ml，无心悸、头晕；无腹痛；四天后清晨空腹时再次出现呕血，量约200ml。1天后出现柏油样大便，余无其他不适既往史：无高血压病史；糖尿病史2年，血糖最高20mmol/L，口服二甲双胍、格列美脲治疗，目前血糖控制在8-11mmol/L家族史：父亲因颅内肿瘤去世（具体不详），二哥肾癌术后3月生育史：产有1女，体健VHLDiseaseArealcase腹部MRI（黄山首康医院2016-2-25）胰腺多发小囊肿占位伴分隔状强化，考虑良性或交界性病变，不排除VHL疾病胰腺囊肿化腹部增强CT（黄山首康医院2016-2-26）胰腺占位，考虑恶性病变腹部增强CT（2016-03-14，长征医院）胰腺多发低度恶性肿瘤并双肾多发肾癌，考虑VHL综合征可能性大胰源性门脉高压形成双肾多发囊肿肝脏多发囊肿；肝右叶低密度灶VHLDiseaseArealcase腹部CTA（2016-03-14，长征医院）上腹部血管三维重建（2016-03-17，长征医院）1926:Lindau

DescribedtheangiomasofCNS

1904:vonHippelFirstdescribedangiomasintheeyeTHEHISTORYOFVHLDISEASEvonHippel-LindauDiseaseLindauSwedish

pathologist

vonHippelGermanophthalmologist1936:ThetermvonHippel-Lindaudiseasewasfirstused.Intheearly1990s,investigatorsattheNCIstudyingfamilieswithVHLdiseaseusedgeneticlinkageanalysistoidentifygermlinemutationsordeletionsintheVHLgeneasthebasisforthisdisease.vonHippel-LindauDisease8THEHISTORYOFVHLDISEASEVHLDiseasevonHippel-LindauDisease--GeneticillnessSlOGAN:

THECUREFORCANCERSINOURGENES.VHLgene:Atchromosome3p25-26asatumorsuppressorforbothsporadicandfamilialformsofclearcellRCC.Thewild-typeVHLproteintargetsHIF

fordegradation.VHLProtein/pVHLMolecularBasispVHLHIF-αuuuHIF-αHIF-αHIF-αHIF-αHIF-αHIF-αHIFβHIFβHIF-αDestructionActiveHIFHormoneRegulatoryElementTargetgeneexpressionHREHIFβHIF-αHypoxiapVHLNormxiapVHLActivityinPhysiologicandPathologicStatespVHLHypoxiaInduciblefactorsHIFS11HIFs.:areintracellularproteinsthatplayanimportantroleinregulatingcellularresponsestohypoxia,starvation,andotherstresses..MolecularBasisHIF-αPI3KAKTmTORRAPTORmLST8GβLHIFβHIFβubiquitinationHypoxicstimulationProteasomedegradationHIF-αHIFβTargetgeneexpressionVEGFTGFαPDGFGlut1HREVEGFTGFαPDGFGlut1ElonginBElonginCGLU2E2Rbx1α

domainβdomainMutationoftheVHLgeneallowsHIF

toaccumulate,leadingtoincreasedexpressionofMutatepVHLHIF-αuuuHormoneRegulatoryElementpVHLDestruction(-)pVHL(+)Unknownmediators(+)VEGFSignalingMechanismsMolecularBasisKDRVEGFPPPPPI3KAKT/PKBP38MAPKKDRRafVEGFTyrosinekinaseinhibitorsmTORinhibitorsKDR(VEGF-R2)VascularpermeabilityEndothelialcellsurvivalEndothelialcellMigrationMEKErKEndothelialcellProliferationVascularEndothelialcellplasmamembraneAntibodiestoVEGForVEGFRKDR=kinasedomainreceptor;mTOR=mammaliantargetofrapamycinErk=extracellularlyregulatedkinase;MAPK=mitogen-activatedproteinkinase;MEK=MAP/Erkkinase;PKB=proteinkinaseB;VEGFR=VEGFreceptorRelationshipsBetweenVHLandmTORMolecularBasisDirectrelationshipbetweenVHLlossandincreasedVEGFactivitymTORindirectlyaffectsHIFandVEGFNotclearwhichmTORactivitiesarerelevanttokidneycancerInhibitionofmTORwithrapamycin-likedrugscanactivateupstreamkinasesPATHOLOGYRCCNotasasinglemalignantneoplasm.Butratherasagroupcomprisingseveraldifferenttumorsubtypes,eachwithadistinctgeneticbasisanduniqueclinicalfeatures.WHOClassificationoftheRCC201614ThegenesassociatedwithRCCLinehan,W.M.andRicketts,C.J.Themetabolicbasisofkidneycancer.Seminarsincancerbiology,23,1(Feb2013),46-55.VEGFSignalingMechanismsCytokineage靶向治疗时代高剂量IL-2阿昔替尼2015依维莫司2013阿昔替尼依维莫司200919922012培唑帕尼贝伐单抗联合IFN-α2007舒尼替尼2006索拉非尼2005替西罗莫司舒尼替尼2007索拉非尼2006纳武单抗2015卡博替尼2016乐伐替尼联合依维莫司2017乐伐替尼联合派姆单抗培唑帕尼2018TargeteddrugsforRCCThe

targetedagentsforrenalcellcarcinoma17TargeteddrugsforRCCThe

targetedagentsforrenalcellcarcinomaGeneralNameCompanyTradeNameFDACFDAPazopanib

培唑帕尼2009.10Everolimus

依维莫司2009.032015.02Axitinib

阿西替尼2012.012015.04Sorafenib

索拉菲尼2005.122008.05Sunitinib

舒尼替尼2006.012006.09飞尼妥英立达多吉美索坦2017.02维全特GeneralNameCompanyTradeNameFDACFDATemsirolimus

替西罗莫司2007.03Bevacizumab

贝伐珠单抗2009.07Notapproved阿瓦斯汀NotapprovedNivolumab

纳武单抗Lenvatinib

乐伐替尼Cabozantinib

卡博替尼NotapprovedNotapprovedNotapproved托瑞赛尔2016.052016.042015.11TargeteddrugsforRCCThe

targetedagentsforrenalcellcarcinomaPembrolizumab派姆单抗Notapproved2018.01MolecularBasisForTargetedApproachesAnti-AngiogenesisTherapy---howtostarveatumor19MolecularBasisForTargetedApproachesTheAngiogenesis20PathologicalAngiogenesis&MMPrelateddisordersRolesofVEGFandmTORInhibitors21MolecularBasisTumorCellTargetCellTranscription/SynthesisHIF

RAPTORmTORVEGFExtracellularSpacePI3KAKTSunitinibSorafenibPazopanibAxitinibibVEGFBevacizumabRAPTORmTORKDRPDGFPDGFREverolimusTemsirolimusEndothelialcell/Pericyte/fibroblastSmoothmuscleEverolimusTemsirolimusDestruction(+)(-)(+)pVHLKDR:VEGF-R2TargetedMolecularAgentsForCCRCCPI3K-AKT-mTORPathway

22EverolimusFKBPPI3KAKTmTORRAPTORmLST8GβLp70S6KPCyclinD1C-MycmRNAtranslationCellsitimuli(eggrowthfactors)HIF

TumorCellExtracellularRTKAngiogenesisanti-angiogeneis转移14Angiogenesisandanti-angiogeneisThemechanismoftargetedtherapySmalltumorNonvascularDormantLargertumorVascularMetastaticpotentialMolecularBasisTheAngiogenesisbalance24Sunitinib

舒尼替尼Pazopanib

帕唑帕尼Axitinib

阿西替尼Sorafenib

索拉非尼Bevacizumab

贝伐珠单抗Lenvatinib

乐伐替尼Cabozantinib

卡博替尼主要作用位点VEGFR、PDGFR、KIT、FLT-3RVEGFR、PDGFRVEGFR、c-KITVEGFR、C-KITVEGFR、c-MET、AXLVEGFR、FGFR、PDGFR、KIT、RETVEGF-APDGFR:platelet-derivedgrowthfactorreceptor血小板衍生生长因子受体FGFR:FibroblastGrowthFactorReceptor成纤维细胞生长因子受体C-MET:hepatocytegrowthfactorreceptor(HGFR)肝细胞生长因子受体名称抑制肿瘤增殖抑制血管生成Angiogenesisandanti-angiogeneisThemechanismoftargetedtherapyPD-1抑制剂纳武单抗免疫检查点分子CTLA-4抑制剂易普利单抗PD-L1抑制剂派姆单抗Immuno-checkpointinhibtorThemechanismoftargetedtherapySunitinibresistance27TargetedMolecularAgentsDrugs--SunitinibSunitinibresistanceisamajorchallengeforadvancedRCC.

晚期肾透明细胞癌一线治疗风险状况好或中等（MSKCC评分）风险状况不良培唑帕尼a贝伐珠单抗+IFN-αa舒尼替尼a索拉非尼b

替西罗莫司a高剂量IL2b舒尼替尼b

培唑帕尼b2017年EAU指南后续治疗EAU2017recommendationsforsystemictherapyinpatientswithmRCCDrugselectionformetastaticRCC一线治疗CCRCCnCCRCC后续治疗NCCN2018V1.0DrugselectionformetastaticRCCINDICATIONSANDUSAGE1.GastrointestinalStromalTumor(GIST)2.AdvancedRenalCellCarcinoma(RCC)3.AdvancedPancreaticNeuroendocrineTumors(pNET)Sunitinib索坦舒尼替尼SUTENT®(苹果酸舒尼替尼胶囊)用法与用量

50mg1/日

4/22/1PFSOS1.晚期肾癌(RCC)2.软组织肉瘤Pazopanib维全特®培唑帕尼适应症VOTRIENT®(培唑帕尼片)用法与用量推荐剂量：800mg/天整片与水同服(请勿掰开或压碎)不与食物同服(至少餐前1小时或餐后2小时)每次调整200mg剂量剂量调整OSSorafenib

多吉美索拉非尼适应症1.晚期肾癌(RCC)2.晚期肝癌(HCC)2.低分化甲状腺癌(DTC)NEXAVAR®(甲苯磺酸索拉非尼片)用法与用量

常规剂量400mgbid增加剂量600mgbid增加剂量800mgbidPFSAxitinib英立达阿西替尼适应症1.晚期肾癌(RCC)INLYTA®(阿西替尼片)用法与用量剂量调整PFSEverolimus

飞尼妥依维莫司适应症1.晚期肾癌(RCC)2.系统性结节性硬化相关血管平滑肌脂肪瘤(TSC-AML)3.胰腺神经内分泌肿瘤(pNET)AFINITOR®(依维莫司片)用法与用量

10mg，1/日1.Afinitor[prescribinginformation].EastHanover,NJ:NovartisPharmaceuticalsCorp;2016.2.Bago-HorvathZ,SieghartW,GruschM,etal.Synergisticeffectsoferlotinibandeverolimusonbronchialcarcinoidsandlarge-cellneuroendocrinecarcinomaswithactivatedEGFR/AKT/mTORpathway.Neuroendocrinol.2012;96(3):228-237.国内依维莫司临床试验L2101InhibitionofTORC1andTORC2Complexes35MolecularBasisRAPTORmTORPI3KAKTRTKIntracellularmTORTorc1complex(rapalogsensitive)RICTORTorc2complex(rapaloginsensitive)AdditionaloncogenicfunctionsExtracellularHIF

CourtesyofWilliamG.KaelinJr.,MDTemsirolimusandeverolimusarerapalogsDoubleAnti-CancerFunctionDoubleAnti-CancerFunction1.Anti-tumorcellproliferation2.Anti-angiogenesisTargetedMolecularAgentsDrugs--Sunitinib36VEGFRVEGFPDGFRPDGFVEGFR1VEGFR2VEGFR3VEGFRαVEGFRβRETKITPLT-3METinRCCMETsignalinghasbeenshowntobeimportantinRCC[a]METcancooperatewithepidermalgrowthfactorreceptor[b]METmutationsdrivethepathologyinhereditarypapillarykidneycancer[a]

PapillarykidneycancerisanidealRCCtumorfort