Genetherapyagainstbraincancer

Promisingresultsfor“targeted”treatmentsagainstglioblastomaMay13,2016AteamfromtheInternationalSchoolforAdvancedStudies(SISSA)inTriestehasobtainedverypromisingresultsbyapplyinggenetherapytoglioblastoma.Testsinvitroandinvivoonmiceprovidedveryclear-cutresults,andmodellingdemonstratesthatthetreatmenttargetsatleastsixdifferentpointsoftumourmetabolism.Genetherapy,atechniquethatselectivelyattacksatumour,mightprovidehopeinthefightagainstthistypeofdeadlycancer,forwhichsurgeryispracticallyimpossibleandchemo-andradiotherapyareineffectiveagainstveryaggressiverecurrences.ThestudywaspublishedinthejournalOncotarget.

Onlyafewdaysago,thepress(especiallyinEnglish-speakingcountries)enthusiasticallyannouncedthepublicationofastudythatdescribedingreatdetailthegeneticsofbreastcancer,adiscoverythataccordingtomanymarksabreakthroughinthebattleagainstthiscancer.Thiskindofnewsconfirmstheimpressionthatinthenearfuturethewaragainstcancerwillbefoughtonthebattlefieldsofgenetics.Italytoo,isworkingonthisfront.AtSISSA,forexample,whereAntonelloMallamaciandhisgrouphavejustpublishedhighlypromisingresultsontheapplicationofgenetherapyagainstglioblastomas,afamilyofbraintumoursamongthemostcommonandaggressive.Adiagnosisofglioblastomaisliterallyequaltoaveryimminentdeathsentence:“surgeryisrarelycurative,asthesetumoursinsinuatethemselvesinhealthytissues,andalsochemo-andradiotherapyhavelittleeffectiveness.Inashortwhile,veryaggressiverecurrencesdevelopandthatmarkstheend”explainsAntonelloMallamaci,SISSAprofessorwhoalsocollaborateswiththeTelethonFoundation.“Ourapproachisradicallydifferent:weintroduceanadditionalcopyofagivengeneintothetumourcellssoastoimpairtheirreproductivecapacityandleadthemtosuicide”.TheideaforthisstudycametoMallamaci–whoisnotanoncologist–afteryearsofcloseinvestigationofaparticulargenecalledEmx2.Oneofthecharacteristicsofthisgene,explainsthescientist,istoinhibitproliferationofastrocytesduringembryonicgrowth.Glialcells,includingastrocytes,arepartofthenervoussystem,wheretheynourishandprotectneuronsandfinelyregulatetheirfunction.“Weknowthatduringtheearlystagesofdevelopmentofthenervoussystemonlyneuronsgrow,whereasglialcellsonlystarttoproliferatewhenneuronalgrowthispracticallycomplete”,explainsCarmenFalcone,SISSAresearchscientistandfirstauthorofthepaper.“InourpreviousstudieswediscoveredthatEmx2isexpressedatveryhighlevelsduringtheneuronalgenerationphase,whereasitsactiondeclinesdramaticallywhentheglialcellsstarttogrow.Sothegenekeepsastrocytegrowthincheckuptoacertainpoint”.Ifitcanblockastrocytes,whynottryanduseittoblockglioblastomas?“Thesetumourssharemanyfeatureswithastroglia”commentsMallamaci,“hencetheideatousethemtoouradvantage.WiththecontributionofISTinGenoa,whichsupplieduswithculturesofvarioustypesofglioblastoma,westarteddoingsomeinvitrotests”.Andthesetestswent“beyondourrosiestexpectations”,explainFalconeandMallamaci:“innearlyallofthesamples,thetumourtissueliterallycollapsedinlessthanaweek.”.Atthispointthestudycontinuedintwodirections.Theteamfirstmodelledinvitrothemolecularmechanismsinterveningbetweenwhenthetherapeuticgeneis“switchedon”andthefinal

effect,findingthatthegeneattackstumourmetabolismatnolessthansixpoints,aresultdefinedas“veryrobust”bytheresearchers.ATrojanhorseinsidethetumourAftertheinvitrostudies,thegroupstarteditsfirstinvivoexperimentsonmice,adoptingalldueprecautionstopreventunacceptablesufferingoftheanimals.“So,topreventdamagetothehealthycells,neuronsandastrocytes,weselectedaspecific‘promotor’,apieceofDNAthatcausesthetherapeuticgenetobecomeactivatedonlyintumourcells,withoutattackingtheothercells,andwereplicatedthesameresultasseeninthefirstinvitrotests”.Genetherapyisbasedontheinsertionofadhocgenesintoahostcell’sgenomesothatthesegenescanfunctioninsidethecellbyborrowingitsgeneticmachinery.Howisabitofgeneticcodeaddedtoalivingcell?Scientistsusethemechanismsnaturallyadoptedbyviruses.Virusesarestrangeentities:althoughtheyhavetheirowngenome,theyarenotabletoduplicate,andreproduce,bythemselves.Forthisreasontheysneakintocells,andinserttheirownDNAintothehostgenome,sothatthecellstartsworkingforthembyduplicatingtheirgenesaswellandformingotherviruses.“Bymakingthevirusharmless,thatis,byemptyingtheshellcontainingitsgenomeandfillingitwiththerapeuticgenes,wecanaddnewgenes,orenhancedversionsofendogenousgenes,tothehostcell”,explainsFalcone.SothatispreciselywhatMallamaciandcolleaguesdid:theyintroducedaparticularlyactiveversionofEmx2intothetumourcells.TheresultssofarhavebeenunequivocalandhavedemonstratedthatEmx2isabletokillthecellsofatleastfourdifferenttypesofglioblastoma,bothinvitroandinvivoinrodents,withoutdamagingthehealthycellsofnervoussystem.Sincetheyalsoobservedthatthetreatmenttargetedmaypointsofthetumourprocess,therearegoodchancesofeffectivelycontrastingthedevelopmentofaggressiverecurrences.“Forthesetoform,therehastobeaprocessofselectionofthestrongesttumourcells.Bytargetingthematavarietyofdifferentpoints,weraisethestandardsinthisselectionprocessand–hopefully–wepreventtherecurrences”,concludesMallamaci.“Nowweplantoextendtheinvivoteststootherglioblastomas.Withalotofhardworkandabitofluckwehopethatinafewyears’timeallthiscantranslateintoatangiblebenefitfortheunfortunatepatientsafflictedbythisdisease”.USEFULLINKS:

• Informationonglioblastoma:http://goo.gl/HKrlzE• OriginalpaperonOncotarget:http://goo.gl/2O96UI

IMAGE:

• Glioblastomacells–Credits:SISSA

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