Patients with newly diagnosed glioblastoma carrying an unmethylated MGMT promoter and incomplete resection face a particularly unfavorable prognosis, for whom the benefit of alkylating chemotherapy is limited. A central driver of recurrence is the rapid restoration of tumor vasculature following radiotherapy.
The authors first established a mechanistic rationale through a stepwise spatial analysis using TCGA bulk RNA sequencing, regional tissue mapping from the Ivy Glioblastoma Atlas Project, multiplex immunofluorescence, and spatial transcriptomics on patient-derived glioblastoma organoids and freshly resected specimens. VEGFA expression tracked closely with hypoxia in perinecrotic regions, while CXCL12 localized predominantly to endothelial cells in the microvascular proliferation and infiltration zones, largely independent of hypoxia. These findings support the hypothesis that angiogenesis and vasculogenesis represent spatially distinct, non-redundant mechanisms of vascular remodeling, providing a rationale for targeting both pathways.
The multicenter phase 1/2 GLORIA trial (NCT04121455), conducted at six German Neuro-Oncology centers, included an expansion arm of six patients receiving radiotherapy together with the CXCL12-neutralizing L-RNA aptamer NOX-A12 (olaptesed pegol) and the VEGF-targeting antibody bevacizumab. The triple combination was well tolerated, with no dose-limiting toxicities and no treatment-related deaths. Median progression-free survival reached 9.1 months and median overall survival 19.9 months, compared with 5.7 and 12.7 months under radiotherapy plus NOX-A12 alone (p = 0.009 and p = 0.021). Two of six patients survived beyond two years, and the median best change from baseline in the highly perfused GBM fraction (FTBhigh) was −98.2%.
Structured imaging assessment was an integral part of the trial. MRI examinations were collected throughout the study and centrally assessed by a board-certified radiologist blinded to study site and clinical status. Within this imaging workflow, mint Lesion supported the structured identification, validation, and longitudinal assessment of target and non-target lesions, alongside other imaging software tools used for image post-processing and interpretation. Radiographic response was assessed according to modified Response Assessment in Neuro-Oncology (mRANO) criteria, including measurements based on the sum of perpendicular diameters.
The authors conclude that the findings provide proof of principle for dual inhibition of CXCL12 and VEGF in combination with radiotherapy and warrant further evaluation in larger studies. The GLORIA trial also illustrates the importance of structured, longitudinal imaging assessment in complex Neuro-Oncology studies, where consistent lesion tracking and standardized response criteria are essential for evaluating treatment response and progression.
For the full spatial analyses, trial design, and safety and survival data, readers are encouraged to consult the original publication:
Giordano, F.A., Layer, J.P., Turiello, R. et al. L-RNA aptamer-based CXCL12 inhibition combined with radiotherapy and bevacizumab in newly-diagnosed glioblastoma: expansion of the phase I/II GLORIA trial. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71362-7
Image from the original publication, licensed under CC BY 4.0. Contains elements from Servier Medical Art (https://creativecommons.org/licenses/by/4.0/).
