SDS2 CHALLENGES IN TREATMENT OF GLIOBLASTOMA: CURRENT CONCEPTS AND THERAPEUTIC PERSPECTIVES

The natural disease course in glioblastoma is grim, in adults as well as in children. To date, there are no options for primary, secondary or tertiary prevention. However, unlike the fatalistic approach generally taken, there are subgroups of patients or individuals clearly benefitting over a variable time from current treatments, radiation and alkylating chemotherapy, as well as experimental precision or immune interventions. This heterogeneity in treatment response reflects the biological heterogeneity of the disease, which needs to be addressed in current preclinical and clinical investigations as well as this identifies primary and acquired treatment resistance as the key challenge in the field of glioblastoma. Importantly, even for most conventional treatments the basic molecular mechanisms for primary or secondary resistance are unknown or incompletely understood. The present view is that progress will be made with a more precise classification and grouping of glioblastoma. The methylation subgroups clearly provide a first step, but further tumor bulk but potentially also subclonal or single-cell analyses might provide further insights and will be a prerequisite to meaningfully interpretable trials. Novel preclinical and translational concepts of glioblastoma in adults reflecting the proposed network architecture of the glioma, but also the glioma-brain interface may for the first time separate options for trial interventions in glioblastoma form the usual mainstream in oncology. Clinical trials of the past years have revealed the potential for further developing a lomustine/temozolomide combination in O6-methylguanine DNA-methyltransferase (MGMT) promoter hypermethylated glioblastoma and allow leaving out temozolomide for glioblastoma harboring an unmethylated MGMT promoter. The latter is not clinical standard, however we should at some point make sure we still understand, why temozolomide is provided in this biological situation and how we make a next step. The field of immunoneurooncology is rapidly growing with preclinical work and trial concepts, but whereas patients with brain metastases seem to benefit from this development, success in glioblastoma is restricted to uncontrolled earl-phase developments.