Targeting apoptosis in cancer cells: improving TRAIL death receptor signaling

Het eiwit TRAIL, dat in het normale immuunsysteem ontstekingen helpt te onderdrukken, is een belangrijk instrument in de strijd tegen kanker. Het bindt zich wel aan gezonde cellen, maar richt er geen schade aan. Als het zich aan een kankercel bindt, kan het deze uitschakelen. Door het gebruik van TRAIL-receptorgerichte middelen kunnen bestaande kankermedicijnen effectiever worden, zo hebben preklinische studies aangetoond. Onderzoek van promovenda Annemieke Meijer laat zien dat door het toepassen van verschillende nieuwe combinatietherapieën met rhTRAIL celdood sterk kan worden verhoogd in onder meer eierstokkanker- en longkankercellen. Ook blijkt dat rhTRAIL de effectiviteit van verschillende vormen van chemotherapie en remming van insulinereceptoren kan vergroten. Ook testte Meijer een nieuw model om de effectiviteit van (combinatie)therapieën te onderzoeken. Vers tumormateriaal van eierstokkankerpatiënten werd in dunne plakjes gesneden, die individueel werden gekweekt en behandeld. Ze toont aan dat de combinatie van een MDM2 remmer, chemotherapie en rhTRAIL leidt tot massale sterfte van kankercellen in gekweekte tumorplakjes. Nader onderzoek moet uitwijzen of deze nieuwe combinatiestrategieën geschikt zijn voor toepassing in de kliniek. Targeting apoptosis, or programmed cell death, is a potential anti-cancer strategy in cancer treatment (1). TNF related apoptosis inducing ligand (TRAIL) is an interesting new agent in this respect, as it selectively induces apoptosis in cancer cells, without inducing toxicity to normal cells. In its recombinant human (rh) form, rhTRAIL forms a stable trimer and can be administered safely to patients. RhTRAIL induces the extrinsic apoptosis pathway in cancer cells via binding to the TRAIL death receptors DR4 (TRAIL-Rl) and DR5 (TRAIL-Rll. which induces receptor trimerization and initiates the apoptotic signal via formation of tht' , death inducing signaling complex (DISC). Primary components of the DISC are trimerized DR4/DR5, FADD, caspase 8 and caspase 10. Subsequently, the caspase cascade is activated resulting in apoptotic cell death. Besides rh TRAIL, DR4-or DR5-selective variants of TRAIL and agonistic DR4 and DR5 antibodies have been designed. Preclinical results with rhTRAIL alone and as part of various combination strategies showed potent antitumor activity. However, preliminary publications of phase 2 randomized trials in which rhTRAIL was combined with different chemotherapeutics, showed no additive effects of rhTRAIL. In this thesis, various new experimental strategies were explored to improve TRAILDR targeted apoptosis induction in cell culture models, in particular of ovarian cancer. In chapter 2 an extensive literature study was presented in which factors influencing the initial steps of the TRAIL apoptosis signaling pathway were discussed. The review focused on mechanisms that modulate DISC assembly and caspase activation at the DISC as a crucial event in eradicating tumor cells. The DR-specific antibodies and rhTRAIL variants that are in development were discussed. In addition, cellular membrane factors such as lipid raft formation that affect DISC formation were addressed. Finally, post-translational modifications of DISC components that affect TRAIL efficacy and the influence of additional cellular proteins that can be recruited to the DISC were discussed. These insights can direct rational design of drug combinations with TRAIL-DR targeting ligands to maximize DISC-apoptosis signaling.