Research findings related to UNITE work package A01

Diffuse gliomas, particularly glioblastomas, are incurable brain tumours. They are characterized by networks of interconnected brain tumour cells that communicate via Ca²⁺ transients. However, the networks’ architecture and communication strategy and how these influence tumour biology remain unknown. Here we describe how glioblastoma cell networks include a small, plastic population of highly active glioblastoma cells that display rhythmic Ca²⁺ oscillations and are particularly connected to others. Their autonomous periodic Ca²⁺ transients preceded Ca²⁺ transients of other network-connected cells, activating the frequency-dependent MAPK and NF-κB pathways. Mathematical network analysis revealed that glioblastoma network topology follows scale-free and small-world properties, with periodic tumour cells frequently located in network hubs. This network design enabled resistance against random damage but was vulnerable to losing its key hubs. Targeting of autonomous rhythmic activity by selective physical ablation of periodic tumour cells or by genetic or pharmacological interference with the potassium channel KCa3.1 (also known as IK1, SK4 or KCNN4) strongly compromised global network communication. This led to a marked reduction of tumour cell viability within the entire network, reduced tumour growth in mice and extended animal survival. The dependency of glioblastoma networks on periodic Ca²⁺ activity generates a vulnerability that can be exploited for the development of novel therapies, such as with KCa3.1-inhibiting drugs.

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Hausmann D, Hoffmann DC, Venkataramani V*, Jung E, Horschitz S, Tetzlaff SK, Jabali A, Hai L, Kessler T*, Azorín DD, Weil S*, Kourtesakis A, Sievers P, Habel A, Breckwoldt MO*, Karreman M*, Ratliff M*, Messmer JM, Yang Y, Reyhan E, Wendler S, Loeb C, Mayer C, Figarella K, Osswald M, Solecki G, Sahm F*, Garaschuk O, Kuner T, Koch P, Schlesner M*, Wick W*, Winkler F*. Autonomous rhythmic activity in glioma networks drives brain tumor growth. Nature. 2023 Jan 613 7942 179 186. *UNITE Principle Investigators

Research findings related to UNITE work package A01

Purpose: The EORTC-26101 study was a randomized phase II and III clinical trial of bevacizumab in combination with lomustine versus lomustine alone in progressive glioblastoma. Other than for progression-free survival (PFS), there was no benefit from addition of bevacizumab for overall survival (OS). However, molecular data allow for the rare opportunity to assess prognostic biomarkers from primary surgery for their impact in progressive glioblastoma.

Experimental design: We analyzed DNA methylation array data and panel sequencing from 170 genes of 380 tumor samples of the EORTC-26101 study. These patients were comparable with the overall study cohort in regard to baseline characteristics, study treatment, and survival.

Results: Of patients’ samples, 295/380 (78%) were classified into one of the main glioblastoma groups, receptor tyrosine kinase (RTK)1, RTK2 and mesenchymal. There were 10 patients (2.6%) with isocitrate dehydrogenase mutant tumors in the biomarker cohort. Patients with RTK1 and RTK2 classified tumors had lower median OS compared with mesenchymal (7.6 vs. 9.2 vs. 10.5 months). O6-methylguanine DNA-methyltransferase (MGMT) promoter methylation was prognostic for PFS and OS. Neurofibromin (NF)1 mutations were predictive of response to bevacizumab treatment.

Conclusions: Thorough molecular classification is important for brain tumor clinical trial inclusion and evaluation. MGMT promoter methylation and RTK1 classifier assignment were prognostic in progressive glioblastoma. NF1 mutation may be a predictive biomarker for bevacizumab treatment.

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Kessler T*, Schrimpf D, Doerner L, Hai L*, Kaulen LD, Ito J, van den Bent M, Taphoorn M, Brandes AA, Idbaih A, Dômont J, Clement PM, Campone M, Bendszus M*, von Deimling A*, Sahm F*, Platten M*, Wick W*, Wick A. Prognostic Markers of DNA Methylation and Next-Generation Sequencing in Progressive Glioblastoma from the EORTC-26101 Trial. Clin Cancer Res. 2023 Jul 26; CCR-23-0926. doi: 10.1158/1078-0432.CCR-23-0926. *UNITE Principle Investigators

UNITE  towards clinical implementation

In response to major changes in diagnostic algorithms and the publication of mature results from various large clinical trials, the European Association of Neuro-Oncology (EANO) recognized the need to provide updated guidelines for the diagnosis and management of adult patients with diffuse gliomas. Through these evidence-based guidelines, a task force of EANO provides recommendations for the diagnosis, treatment and follow-up of adult patients with diffuse gliomas. The diagnostic component is based on the 2016 update of the WHO Classification of Tumors of the Central Nervous System and the subsequent recommendations of the Consortium to Inform Molecular and Practical Approaches to CNS Tumour Taxonomy – Not Officially WHO (cIMPACT-NOW). With regard to therapy, we formulated recommendations based on the results from the latest practice-changing clinical trials and also provide guidance for neuropathological and neuroradiological assessment. In these guidelines, we define the role of the major treatment modalities of surgery, radiotherapy and systemic pharmacotherapy, covering current advances and cognizant that unnecessary interventions and expenses should be avoided. This document is intended to be a source of reference for professionals involved in the management of adult patients with diffuse gliomas, for patients and caregivers, and for health-care providers.

 

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Weller M, van den Bent M, Preusser M, Le Rhun E, Tonn JC, Minniti G, Bendszus M*, Balana C, Chinot O, Dirven L, French P, Hegi ME, Jakola AS, Platten M*, Roth P, Rudà R, Short S, Smits M, Taphoorn MJB, von Deimling A*, Westphal M, Soffietti R, Reifenberger G, Wick W*. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2020 Dec 8. doi: 10.1038/s41571-020-00447-z. Online ahead of print.Nat Rev Clin Oncol. 2020.PMID: 33293629

*UNITE Principle Investigators

Research findings related to UNITE work package B01

Intrinsic malignant brain tumors, such as glioblastomas are frequently resistant to immune checkpoint blockade (ICB) with few hypermutated glioblastomas showing response. Modeling patient-individual resistance is challenging due to the lack of predictive biomarkers and limited accessibility of tissue for serial biopsies. Here, Michael Platten et al. investigate resistance mechanisms to anti-PD-1 and anti-CTLA-4 therapy in syngeneic hypermutated experimental gliomas and show a clear dichotomy and acquired immune heterogeneity in ICB-responder and non-responder tumors. They made use of this dichotomy to establish a radiomic signature predicting tumor regression after pseudoprogression induced by ICB therapy based on serial magnetic resonance imaging. They provide evidence that macrophage-driven ICB resistance is established by CD4 T cell suppression and T_reg expansion in the tumor microenvironment via the PD-L1/PD-1/CD80 axis. These findings uncover an unexpected heterogeneity of response to ICB in strictly syngeneic tumors and provide a rationale for targeting PD-L1-expressing tumor-associated macrophages to overcome resistance to ICB.

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Aslan K, Turco V, Blobner J, Sonner JK, Liuzzi AR, Núñez NG, De Feo D, Kickingereder P*, Fischer M, Green E, Sadik A, Friedrich M, Sanghvi K, Kilian M, Cichon F, Wolf L, Jähne K, von Landenberg A, Bunse L*, Sahm F*, Schrimpf D, Meyer J, Alexander A, Brugnara G, Röth R, Pfleiderer K, Niesler B, von Deimling A, Opitz C, Breckwoldt MO, Heiland S, Bendszus M*, Wick W*, Becher B, Platten M*. Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas. Nat Commun. 2020 Feb 18;11(1):931. *UNITE Principle Investigators