Van kleuterklas naar laboratorium: het gaspedaal van leukemie uitschakelen
Een van mijn klasgenootjes in de kleuterschool moest vechten tegen leukemie, kort nadat ik mijn ‘Moeke’ aan een agressieve leukemie had verloren. Op dat moment wist ik: “ik wil later het verschil maken voor patiënten.” Die woorden zijn me altijd bijgebleven. Twintig jaar later stapte ik het laboratorium voor de Biologie van Leukemie binnen, niet als patiënt of familielid, maar als onderzoeker. Tijdens mijn thesis onderzocht ik negen nieuwe kandidaat-geneesmiddelen. Twee daarvan bleken bijzonder veelbelovend en worden vandaag al verder onderzocht. Dit kan een veelbelovende stap zijn richting gerichtere behandelingen met mogelijk minder afhankelijkheid van intensieve chemotherapie.
Leukemie is nog steeds de meest voorkomende kanker bij kinderen. De afgelopen decennia zijn de overlevingskansen sterk gestegen, dankzij steeds beter afgestemde intensieve chemotherapie. Toch hervalt 15% tot 20% van de kinderen, waardoor de overlevingskansen aanzienlijk dalen. Bovendien is chemotherapie gericht op alle snel delende cellen, inclusief gezonde cellen, wat zorgt voor heel wat bijwerkingen. Veel patiënten ervaren vermoeidheid, misselijkheid, haaruitval en een verminderde afweer, waardoor kinderen gevoeliger worden voor infecties. De nood aan meer gerichte behandelingen is voor mij geen abstract wetenschappelijk probleem. Ik heb van dichtbij gezien wat kanker met patiënten en hun omgeving doet.
Rode en witte bloedcellen onder de microscoop. Kanker in de witte bloedcellen wordt leukemie genoemd.
Een gaspedaal dat blijft ingedrukt
Mijn onderzoek richtte zich op een specifieke vorm van kinderleukemie: hoog-hyperdiploïde B-cel acute lymfatische leukemie (HeH B-ALL). Deze vorm is de meest voorkomende vorm van B-ALL bij kinderen en treft ongeveer drie op de tien kinderen met B-ALL. Deze specifieke vorm van leukemie wordt gekenmerkt door extra chromosomen en dus extra genetisch materiaal (DNA) in de B-cellen. Extra genetisch materiaal verstoort de normale werking van de cel, waardoor veel cellen niet meer goed kunnen functioneren en zelfs afsterven. Cellen die bovenop het extra genetisch materiaal ook fouten opstapelen in hun groeisysteem, zoals het RAS-systeem, krijgen zo een voordeel. Zo’n fout in het RAS-systeem kan ervoor zorgen dat het gaspedaal van de cel als het ware blijft ingedrukt. Het eindresultaat is dat bloedcellen zich abnormaal ontwikkelen, hun normale functies niet meer uitoefenen en ongecontroleerd blijven delen. De vraag die mij daarom drijft, is eenvoudig, maar tegelijk complex: kunnen we de ongeremde leukemiecellen uitschakelen?
De voet van het gaspedaal halen
In mijn onderzoek maakte ik celmodellen in het labo die exact dezelfde fouten in het RAS-systeem bevatten. Nadien bekeek ik welke nieuwe geneesmiddelen (RAS-remmers) het meest geschikt waren om die ontspoorde groei weer te blokkeren. Ik testte negen veelbelovende kandidaat-geneesmiddelen, elk met een andere strategie om het ontspoorde RAS-systeem uit te schakelen. Sommige remmen het RAS-eiwit rechtstreeks af, andere zorgen ervoor dat het op de foute plaats in de cel terechtkomt of grijpen verderop in dezelfde signaalroute in. Daarnaast testte ik geneesmiddelen die het eiwit rechtstreeks naar de afvalcontainer van de cel sturen, waardoor het RAS-eiwit wordt afgebroken. Ik onderzocht bij elke strategie zowel hoe sterk de geneesmiddelen de groei van de leukemiecellen remden, als hun effect op het RAS-signaal zelf en hun toxiciteit.
Cellen in het labo worden in leven gehouden in een plaat.
Verschillende geneesmiddelen slaagden erin het ontspoorde groeisignaal stil te leggen, zonder gezonde cellen ernstig te beschadigen. Zeven van de negen kandidaat-geneesmiddelen toonden veelbelovende resultaten. Uiteindelijk bleven twee duidelijke toppers over. De sterkste resultaten werden behaald met Daraxonrasib, dat het RAS-eiwit direct blokkeert, en Trametinib, dat het signaal verderop stopt. Opvallend was dat beide geneesmiddelen effectief waren, ongeacht welke fout aanwezig was in het RAS-systeem. Andere geneesmiddelen gaven ook veelbelovende resultaten, maar enkel wanneer bepaalde fouten in het RAS-systeem voorkwamen. Twee van de negen geneesmiddelen vielen af omdat ze toxische effecten hadden of omdat ze de celgroei niet konden blokkeren.
Van proefbuis naar patiënt
Tijdens mijn onderzoek testte ik deze geneesmiddelen in het labo. De volgende stap is testen in patiëntmodellen. Deze modellen zijn afgeleid van echte leukemiecellen. Zo kunnen we nagaan of onze resultaten uit het labo ook standhouden in een realistischer model van leukemie. Het mooiste resultaat? Daraxonrasib en Trametinib bleven niet beperkt tot mijn thesis. Intussen worden beide geneesmiddelen, op basis van deze resultaten, al getest in patiëntmodellen die in ons labo zijn ontwikkeld. Dat betekent dat mijn thesis niet eindigt op papier, maar vandaag al verder leeft in nieuw onderzoek.
Als de volgende resultaten positief zijn, kunnen klinische studies een volgende stap worden. Pas daarna kan worden onderzocht of deze geneesmiddelen uiteindelijk een plaats kunnen krijgen in de behandeling van patiënten. Omdat deze RAS-remmers zich richten op een specifiek groeisysteem van de leukemiecellen, hopen we dat ze in de toekomst een gerichtere behandeling met mogelijk minder bijwerkingen kunnen bieden dan klassieke chemotherapie. Dat mijn onderzoek vandaag al deel uitmaakt van vervolgonderzoek naar betere behandelingen voor kinderen met leukemie, betekent voor mij bijzonder veel.
Twintig jaar geleden ontstond mijn droom in een kleuterklas. Vandaag staat die droom tussen proefbuizen en petrischaaltjes. En morgen? Dankzij mijn doctoraatsopleiding aan de KU Leuven krijg ik de kans om die droom verder na te jagen en me verder te verdiepen in leukemieonderzoek. Want zolang kinderen met leukemie blijven vechten, blijf ik zoeken naar betere behandelingen.
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