Several discoveries both on the morphological and functional cellular level have fundamentally changed our understanding of glioblastoma biology over the last years. Most notably, tumor microtubes (TMs) as ultralong membrane protrusions enable glioblastoma cells to assemble to a syncytial microinvasive communicating network. TM-supported neurogliomal synapses (NGS) have been shown to integrate glioblastoma cells into neural circuits which foster malignant growth and cellular invasiveness. The authors speculate to what extent these novel insights into the malignant network might impact future standard of care and attempt to conceive a multimodal treatment regime based on current translational efforts and ongoing clinical trials.

A therapeutic outlook was conceptualized with regard to the following basic principals deduced from abovementioned discoveries: 1) Morphological isolation on the single cell level via inhibition of TM-based spatial network architectures. 2) Functional isolation on the single cell level via inhibition of TM-mediated intercellular cytosolic exchange and inhibition of NGS activation. 3) Greatest possible removal of the microinvading tumor cell front far beyond MRI-detectable abnormalities.

Three multicenter clinical trials in the light of abovementioned principles are being designed, are recruiting or are at the stage of initiation: The MecMeth/NOA-24 phase I/II trial evaluates meclofenamate (MFA) as a potential TM-targeted drug. MFA has recently been shown to exert a morphological and functional breakdown within TM-based glioblastoma networks by an inhibition of TM outgrowth and TM-mediated intercellular cytosolic traffic. The PERSURGE trial will analyze the effects of perampanel as a NGS-inhibitory drug regarding functional connectivity and radiological tumor growth kinetics. The ATLAS/NOA-29 trial is designed as the first prospective trial to evaluate supramarginal resection for a potential survival benefit compared to a gross-total resection regime in temporal glioblastoma.

Reminiscent of the Alcatraz Federal Penitentiary, where inmates had to face 1) a spatial isolation in single cells, 2) a functional isolation by the ban of interpersonal communication and 3) a safety-margin to the mainland by the sea as an insuperable barrier, the authors propose the Alcatraz-Strategy as a multimodal therapeutic approach – aimed at fighting glioblastoma‘s long-distance connectivity and microinvasive capacity.