Mounting an attack on the glioblastoma triad: proliferation, invasion and resistance

Abstract

Despite decades of research, glioblastoma (GBM) remains a formidable opponent and patients suffering from this primary brain tumor still have a dismal prognosis. Following extensive treatment involving surgery, ionizing radiotherapy and temozolomide chemotherapy, the median overall survival is still a mere 15 months. Large-scale efforts to characterize GBM have delivered major insights into its genomic landscape, epigenetic profile and micro-environmental context. Together, these studies have revealed that GBM is a collection of diseases. Today, we recognize up to 5 different subtypes of glioblastoma based on genomic, epigenomic and expression profiling: classical, proneural, G-CIMP, mesenchymal and neural GBM. Moreover, GBMs are very heterogeneous and typically consist of more than 1 subtype. Importantly, these subtypes appear to exhibit a high level of plasticity, as GBM cells can rapidly change their subtype as a result of selective pressures such as anticancer treatment. Although there is substantial heterogeneity, the aforementioned characterization efforts have also pinpointed various commonalities between GBMs that offer potential handles for therapeutic approaches. This thesis investigates several of these new approaches, but also studies ways to further improve the efficacy of classical treatment modalities such as chemotherapy and radiotherapy. The ultimate aim is to mount a full-blown attack on three main pillars of GBM biology: uncontrolled proliferation, an unparalleled level of invasion into surrounding healthy brain tissue, and tremendous resistance to therapy. Together, these properties form the glioblastoma triad. This thesis investigates all three pillars separately and identifies efficient ways to attack each individually. However, while modest antitumor efficacy can be achieved by individual targeting, an intelligently designed therapeutic approach that attacks the entire glioblastoma triad will be necessary to achieve durable clinical responses.