Interpretation of differential drug sensitivities in paired patient-derived newly-diagnosed and recurrent glioblastoma cell lines

Marine Van der Voordt
Persbericht

De zoektocht naar de meest efficiënte behandeling voor individuele glioblastoompatiënten

Dit project focust op de ziekte die Beau Biden, zoon van VS president Joe Biden, en nog vele andere patiënten, het leven kostte: glioblastoom, een extreem agressieve hersentumor. De ziekte begint met algemene symptomen zoals hoofdpijn en misselijkheid. Na enige tijd wordt de hoofdpijn erger en gaat het gepaard met een verminderd zicht en bewustzijnsdalingen, tot de diagnose van glioblastoom wordt vastgesteld. Met een gemiddelde overleving van slechts 15 maanden na de diagnose staat glioblastoom terecht bekend als de meest gevreesde hersentumor.

Het lot van glioblastoompatiënten

De behandeling is voor elke glioblastoompatiënt dezelfde. Eerst wordt de tumor verwijderd in een uiterst delicate operatie. Alle tumorcellen weghalen is echter een onmogelijke taak vanwege hun de invasieve aard. Na de operatie wordt de patiënt behandeld met de standaardbehandeling, bestaande uit temozolomide (TMZ) en radiotherapie (RT) met als doel om de resterende tumorcellen te vernietigen. Het toevoegen van TMZ aan de standaardbehandeling heeft de overleving met slechts 2 maanden verbeterd. Ondanks deze behandeling hervallen alle patiënten en slaagt de tumor er dus toch in om na gemiddeld 9 maanden na de operatie terug te groeien in de hersenen. Dit is te wijten aan o.a. de aanwezigheid van radio -en chemoresistente stamcellen in zulke tumoren. Voor recurrente GBM tumoren is er geen behandeling mogelijk. Ondanks talloze ondernemingen is men er nog niet in geslaagd om de overlevingskans te verbeteren.

Precisiegeneeskunde voor glioblastoom

Ook de heterogeniteit tussen patiënten is enorm. Toch krijgen alle glioblastoompatiënten, ongeacht de aard van de tumor, dezelfde standaardbehandeling, waardoor slechts een klein deel van de patiënten hier positief op reageert. Een efficiëntere aanpak zou precisiegeneeskunde kunnen zijn, waarin de meest optimale behandeling wordt toegeschreven aan afzonderlijke patiënten louter op basis van de aan-of afwezigheid van specifieke genetische kenmerken van hun tumor. Hoewel dat in andere soorten kankers precisiegeneeskunde al tot doorbraken geleid heeft, zijn pogingen om effectieve behandelingen te vinden op basis van het genetische profiel van glioblastomen vruchteloos gebleven.

Patient-Derived Cellijn (PDCL): de uitweg naar effectieve behandelingen?

Om de meest efficiënte en kosteneffectieve behandeling te geven aan individuele patiënten, zouden mogelijke therapieën ex vivo getest moeten worden op levende cellen afkomstig van de tumor. In het Laboratorium voor Precisiegeneeskunde in Leuven worden cellijnen afgeleid van verwijderde hersentumoren van verschillende patiënten (Figuur 1). Na de operatie wordt een biopsie van de tumor naar het laboratorium gebracht die onmiddellijk gedissocieerd wordt tot afzonderlijke cellen. Deze worden tenslotte in een groeimedium gebracht - al dan niet met succes - verwerkt tot een Patient-Derived Cellijn (PDCL). Elke PDCL wordt bovendien genetisch gekarakteriseerd waardoor wijzigingen in het DNA (mutaties bijvoorbeeld) van de tumorcellen gekend is. Het bezit van de PDCLs is een sterke troef aangezien er nu rechtstreeks een reeks van potentiële therapieën op deze cellen kunnen worden getest. Bovendien waren voor dit project gepaarde PDCLs gegenereerd, afkomstig van zowel de newly-diagnosed (ND) als van de recurrente tumor van dezelfde patiënt (Figuur 2).

Figuur 1. Generatie van een Patient-Derived Cellijn (PDCL). De tumor van een glioblastoompatiënt wordt operatief verwijderd. Vervolgens wordt een biopsie genomen, die gedissocieerd wordt in afzonderlijke cellen. Deze worden verwerkt tot PDCL.Figuur 2. Verloop van de glioblastoompatiënt. Na de diagnose van glioblastoom (GBM) wordt de tumor verwijderd in een eerste operatie. Een biopsie van deze tumor wordt verwerkt tot een PDCL. Na de operatie krijgt de eerste patiënt de standaardbehandeling toegediend (TMZ en RT). Na gemiddeld 10 maanden treedt er recurrentie op, wat wil zeggen dat de tumor opnieuw groeit (recurrent GBM). Indien mogelijk wordt deze opnieuw verwijderd en verwerkt tot een recurrent PDCL.

In dit onderzoek werden daarom gepaarde PDCLs afkomstig van de  blootgesteld aan bestaande therapieën. Op basis van de verschillen in gevoeligheid tussen de PDCLs werden de werkzaamheden van de verschillende medicijnen gelinkt aan genetisch profiel. Zo kunnen bepaalde genetische eigenschappen worden gevonden (biomerkers) die de gevoeligheid aan een bepaalde therapie kunnen verklaren.

Zo vertoonden de PCDLs inderdaad verschillende gevoeligheden aan de TMZ (Figuur 3). TMZ werkt door middel van selectieve methylering van DNA waardoor de celdeling van de tumorcellen blokkeert. Bij TMZ kon deze gevoeligheid verklaard worden door de activiteit van MGMT. Het MGMT-eiwit  verwijdert echter de methylering waardoor het effect van TMZ teniet wordt gedaan. De activiteit van MGMT is dus een belangrijke factor voor de gevoeligheid aan TMZ. Een andere therapie die op de PDCLs werd getest, was AMG 232. Deze molecule reactiveert het tumorsuppressorgen p53. Hieruit volgde dat de PCDLs die een mutatie hadden in p53, niet gevoelig waren aan AMG 232, terwijl de PDCLs met het intacte gen, wel gevoeligheid vertoonden (Figuur 4). Een derde therapie was GPP 78, die het metabolisme van de tumorcellen blokkeert. Hieruit bleek dat hoe hoger de expressie van het NAPRT-eiwit, hoe minder gevoelig de PDCLs waren voor GPP 78 (Figuur 4).

Figuur 3. Het effect van TMZ op gepaarde PDCLs. De blauwe curve is een PDCL van de ND tumor, waarin het aantal levende cellen licht afneemt bij een toenemende concentratie TMZ. De corresponderende recurrente PDCL is resistenter tegen TMZ. Dit kan verklaard worden door het verschil in de MGMT-activiteit tussen beide PDCLs. Figuur 4. Het effect van AMG 232 op gepaarde PDCLs. De ND PDCL (blauw) waarin het p53 gen intact is, is gevoeliger dan de overeenkomstige recurrente PDCL (rood) waarin p53 gemuteerd is.

 

Besluit

Deze studie bracht verschillende niet-standaard chemotherapeutica naar voren die werkzaamheid aantonen in PDCLs en het potentieel hebben om snel in klinische onderzoeken te worden opgenomen. Door dit te doen met bestaande medicijnen kan er sneller naar de meest optimale behandeling worden geschakeld met maximale doeltreffendheid en minimale neveneffecten. Er zijn nog wel een aantal belangrijke hindernissen te nemen. Aangezien het genereren van een PDCL maanden kan duren, moet er gezocht worden naar een reproduceerbaar model waarop kort na de operatie van de patiënt verschillende therapieën kunnen worden getest. Zo zou de behandelende arts de meest optimale behandeling kunnen toeschrijven aan GBM patiënten, wat tot een betere levensverlenging kan zorgen voor deze ziekte en kan bijdragen aan de harde strijd tegen kanker.

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Universiteit of Hogeschool
Bioingenieurswetenschappen
Publicatiejaar
2021
Promotor(en)
Frederik De Smet
Kernwoorden
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