Magic-cancer-bullet

Magiccancerbullet:HowatinyorangepillisrewritingmedicalhistoryKinases:TheTargetIn1983,AlexMatter,the“Bulldozer”,wasrecruitedastheheadofthenewlyestablishedOncologyUnitinCiba-Geigy,Basel,Switzerland.Atthattime,cancerresearchprogramswerenottakenseriously,perhapsrightfullyso:Nodrugsforcancerworked,sothevastmajorityofpeopledied.Whileotherphysicianspecialistscuredormadepatientsfeelbetter,oncologists,intryingtohelppatientswithcancerdrugs,usuallymadepatients’livesmoremiserable.Withthe“carpetbombing”approach,chemotherapydestroyedeverythinginitspath,bothcancerousandnormalcells.Chemotherapyweakenedpatientsandhardlyimprovedthequalityofthepatients’livesintheirremainingtimetolive.AlexMatterwasdisappointedwithwhatwasavailabletotreatcancerpatientsandwasdeterminedtofindabettertreatmentorevenacureforcancer.Under“thespellofsomeChinesephysiciansaswellassomeoldmedicalfriendsfromBasel”,Alexincreasinglybelievedthatkinasescouldbeagoodtargetforcancertreatment.TheChineseandBaselscientistshadpointedoutthatkinasesareinvolvedincellproliferation,butnodirectlinkbetweencancerandkinaseswasevidentatthattime.Inthe1980s,mostpharmacologistsremainedunexcitedabouttheprospectsofkinasesbeingacancertarget.Firstofall,therearemorethan150kinasesparticipatingincellularfunctionsinbothnormalandcancercells.Second,kinasesusuallycomprisetheinteriorportion(domains)ofreceptors.Totargetkinases,drugshavetotraversethecellmembraneintocellstobindtothekinase,whichwasconsideredunattainableatthattime.Despitetheskepticism,Matterstillwantedtotry.HewasencouragedbyanabstractinwhichJapanesescientistshaddescribedthediscoveryofanaturalcompoundcalledstaurosporine,extractedfrommushrooms,thathadinhibitedtheactivityofmanykinases.Alexwasdelightedandpressedon.Itwasanoutlandishideabackthen.TheDiseaseThefirstbreakthroughstudyofchronicmyeloidleukemia(CML)camein1960.Dr.PeterNowelloftheUniversityofPennsylvaniaSchoolofMedicineatPhiladelphiaandDr.DavidHungerfordofTheInstituteforCancerResearch(nowFoxChaseCancerCenter)alsoatPhiladelphiadiscoveredthat,inCML,whitebloodcellspossessedachromosomethatwasshorterthanusualanddidnotappeartobelongtoanyoftheknown23chromosomes.Theytermeditthe“Philadelphiachromosome,”whichwasfoundin95%ofCMLpatients.LateritwasfoundthatthePhiladelphiachromosomewasashortenedchromosome22.In1973,Dr.JanetRowleyoftheUniversityofChicagodiscoveredthatCMLcellshadanextrapieceofchromosomeonchromosome9andthattheextrapieceisexactlythepiecemissingfromchromosome22(Philadelphiachromosome).Moreprecisely,thetailofagene(Abelson,Abl)fromchromosome9istranslocatedontotheheadofanothergene(breakpointclusterregion,Bcr)onchromosome22andthuscreatedtheBcr-Abloncogene.In1986and1987,Dr.DavidBaltimore,thenattheWhiteheadInstituteforBiomedicalResearch,MITandnowPresidentofTheCaliforniaInstituteofTechnology,andhisassociatesdiscoveredthattheoncogeneBcr-Ablencodesatyrosinekinase,oneofthemostcommonreceptor-associatedkinaseswhosecascadeofsignaltransductionsupontheactivationofreceptorsregulatescellgrowthanddivision.TheconnectionwasmadethatBcr-AbltyrosinekinasecausesCML,thecancer.SincetheAblportionofBcr-Ablgeneismovedawayfromitsnatural“head”(containinginhibitoryregulatoryelements),theBcr-Abltyrosinekinaseisdevoidofthenormalchecksandbalancesandsois“switchedon”allthetime.Itphosphorylatesuncontrollablyitsdownstreamsubstrateproteinsinthesignaltransductioncascade,resultingincontinuouscellgrowthanddivision,andultimatelytheleukemia.Therapidlyandendlesslydividingwhitebloodcells’enormouspresenceinbonemarrowandtheperipheralbloodimposesa“cancerous”effectonthedevelopmentofotherbonemarrow-derivedcells.Normally,thenumberofwhitebloodcellsis4,000-10,000percubicmillimeterofperipheralblood.InCMLpatients,thenumbercangoashighashundredsofthousands.CMLhasthreephases:Chronic,accelerated,andblastcrisis.TheParadigmThoughtyrosinekinasesingeneralwerethefocusofresearchasadrugtargetforcancertreatmentatCiba-Geigy,Bcr-Ablwasinitiallynotincludedfordrugtargetresearchbecausethereareonlyasmallnumberofpatientstosupportthedrug.Forexample,thereareabout5,000newCMLcasesannuallyintheU.S.,averysmallportionofallcancerpatients.Fromtheverybeginning,thecommercialworthinessofadrugbeingdevelopedforCMLwasquestionedanddebated,especiallywhenthereweresetbacksduringthecourseofresearchanddevelopment.ThelogicwentthatonehastofinddrugsthatspecificallyinhibittyrosinekinasesassociatedwithgrowthanddivisionofcancercellsandthatfindingdrugsspecificallyforBcr-Abltyrosinekinasewasnotworthallthetrouble.OntheothersideoftheAtlanticOceanatDana-FarberCancerInstitute,Boston,Dr.BrianDrucker,workinginDr.TomRoberts’laboratory,wasalsointerestedintargetingtyrosinekinasesfortreatingcancer.Druckerinitiallydidnotbelievethatonecouldfindadrugthatcouldselectivelyinhibitcertaintyrosinekinasesbutnotothers.However,astudypublishedinSciencebyDr.AlexanderLevitzkiandhisassociatesfromIsraelchangedDrucker’sbelief.Dr.Levitzkifoundthattheywereabletoselectivelyinhibittheepidermalgrowthfactorreceptor(EGFR),atyrosinekinasereceptor.In1988,NickLydonwastheheadofthetyrosinekinaseprograminAlexMatter’soncologyd