Glioblastoma as a dynamic tumor ecosystem: from molecular alterations to therapeutic translation.
- 1Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, Hradec Kralove, 500 05, Czech Republic. [email protected].
- 2Department of Toxicology and Military Pharmacy, Military Faculty of Medicine, University of Defence, Trebesska, 1575, Hradec Kralove, 500 01, Czech Republic. [email protected].
Abstract
For more than a century after its initial description, glioblastoma (GBM) has remained one of the most therapeutically refractory human malignancies, resembling an almost impregnable fortress against modern oncology. Despite extensive molecular characterization and identification of numerous actionable targets, survival outcomes have improved only marginally. GBM is characterized by profound spatial and cellular heterogeneity, adaptive signaling rewiring, extensive phenotypic plasticity, an immunosuppressive tumor microenvironment, and major pharmacological constraints imposed by the blood-brain barrier. This review examines the resulting disconnect between biological rationale and clinical outcome through three interrelated translational principles that determine whether mechanistically compelling therapies can achieve meaningful clinical benefit in GBM. First, who is treated and what is biologically active: therapeutic efficacy depends on matching patients to functional pathway dependencies beyond static molecular alterations. Second, whether the drug reaches and modulates its intended target: candidate therapies must achieve sufficient intratumoral exposure and demonstrate target modulation. Third, how the tumor adapts under therapeutic pressure: durable efficacy requires accounting for receptor tyrosine kinase switching, phenotypic plasticity, immune adaptation, and spatial escape. By linking these principles to the molecular, spatial, and pharmacological organization of GBM, this review frames the disease as a dynamic tumor ecosystem and provides a framework for interpreting recurrent clinical failure and guiding more biologically informed therapeutic development.
Related
- Personalized Therapeutic Strategies in Glioblastoma: Bridging Molecular Markers and In Vivo Observations for Targeted Treatment
- Glioblastoma stem cell–immune microenvironment crosstalk: molecular mechanisms and therapeutic opportunities
- Frontier therapeutic strategies and molecular mechanisms of glioblastoma (Review).
- Ferroptosis in cancer: molecular mechanisms, tumour microenvironment, therapeutic resistance, and clinical translation.
- Anatomical and Molecular Foundations of the Gut–Brain Axis in Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Translation
BibTeX
@article{gorecki2026glioblastoma,
title = {{Glioblastoma as a dynamic tumor ecosystem: from molecular alterations to therapeutic translation.}},
author = {Lukas Gorecki},
journal = {Experimental hematology \& oncology},
year = {2026},
month = oct,
doi = {10.1186/s40164-026-00854-5},
url = {https://europepmc.org/article/MED/42958602},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Glioblastoma as a dynamic tumor ecosystem: from molecular alterations to therapeutic translation.
AU - Lukas Gorecki
PY - 2026
DA - 2026/10/28
JO - Experimental hematology & oncology
DO - 10.1186/s40164-026-00854-5
UR - https://europepmc.org/article/MED/42958602
AB - For more than a century after its initial description, glioblastoma (GBM) has remained one of the most therapeutically refractory human malignancies, resembling an almost impregnable fortress against modern oncology. Despite extensive molecular characterization and identification of numerous actionable targets, survival outcomes have improved only marginally. GBM is characterized by profound spatial and cellular heterogeneity, adaptive signaling rewiring, extensive phenotypic plasticity, an immunosuppressive tumor microenvironment, and major pharmacological constraints imposed by the blood-brain barrier. This review examines the resulting disconnect between biological rationale and clinical outcome through three interrelated translational principles that determine whether mechanistically compelling therapies can achieve meaningful clinical benefit in GBM. First, who is treated and what is biologically active: therapeutic efficacy depends on matching patients to functional pathway dependencies beyond static molecular alterations. Second, whether the drug reaches and modulates its intended target: candidate therapies must achieve sufficient intratumoral exposure and demonstrate target modulation. Third, how the tumor adapts under therapeutic pressure: durable efficacy requires accounting for receptor tyrosine kinase switching, phenotypic plasticity, immune adaptation, and spatial escape. By linking these principles to the molecular, spatial, and pharmacological organization of GBM, this review frames the disease as a dynamic tumor ecosystem and provides a framework for interpreting recurrent clinical failure and guiding more biologically informed therapeutic development.
SN - 2162-3619
ER -