Identificatie en ontwikkeling van nieuwe behandelingsmogelijkheden voor glioblastoom

Glioblastoma (GBM) is the most aggressive primary brain cancer in adults. Median survival is approximately 15 to 18 months, despite maximal surgical resection, followed by radiotherapy and chemotherapy. Therapeutic progress is limited by extensive inter- and intratumoral heterogeneity, transcriptional plasticity, and restricted drug delivery imposed by the blood-brain barrier. Consequently, there is an urgent need for novel treatment strategies that can overcome these complications. Nuclear-cytoplasmic transport is a central regulatory process in which proteins and RNA species, including tumor suppressor proteins and cell cycle regulators, are transport out of the nucleus into the cytoplasm. Exportin 1 (XPO1), the principal nuclear export receptor for numerous tumor suppressor proteins and growth regulatory factors, is overexpressed or dysregulated in many malignancies, including GBM, and associated with poor prognosis. Increased nuclear export of key XPO1 cargo proteins results in their functional inactivation and supports unchecked proliferation and resistance to apoptosis. Importantly, XPO1 function represents a particularly compelling therapeutic target in GBM because it operates as a core, nonredundant cellular mechanism rather than a lineage- or state-specific pathway. Pharmacologic inhibition of XPO1 therefore offers a mechanistically grounded strategy to destabilize multiple tumor-survival networks simultaneously and force re-engagement of suppressed tumor-control pathways. Because nuclear export is an essential and centrally regulated process required across diverse cellular states, XPO1 inhibition is inherently less vulnerable to the intratumoral heterogeneity and adaptive plasticity that characterize GBM. Although the first-in-class XPO1 inhibitor selinexor clinically validated the therapeutic potential of nuclear export blockade, its utility is often constrained by dose-limiting toxicities, and further development of nuclear export inhibitors in GBM seems halted at the moment. This project focuses on FR-027, a novel XPO1 inhibitor with distinct chemical and mechanistic properties. FR-027 shows in vitro potency comparable to selinexor and second-generation inhibitor eltanexor in multiple tumor types but engages XPO1 through a reversible covalent interaction and does not induce proteasomal degradation of XPO1. The resulting shortened target engagement profile may increase tolerability of the compound compared to existing XPO1 inhibitors. In addition, FR-027 is orally bioavailable and efficiently penetrates the blood-brain barrier, positioning it as a promising candidate for the treatment of central nervous system malignancies such as glioblastoma. The goal of this project is to evaluate the translational potential of FR-027 and to identify genetic determinants of the cellular response to XPO1 inhibition in GBM. Specifically, this work investigates the in vivo therapeutic efficacy of FR-027 in murine cancer models, assesses its tolerability under repeated dosing in mice, and systematically interrogates genetic regulators of XPO1 inhibitor sensitivity using genome-wide CRISPR-Cas9 loss-of-function screens in patient-derived GBM cell lines. Collectively, this project aims to advance nuclear export inhibition, and FR-027 in particular, as a rational and broadly applicable therapeutic strategy for GBM and other cancers with a high unmet medical need.