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Tumor Discovery

REVIEW ARTICLE
Targeting glioblastoma invasion and therapy

resistance: Emerging trends and molecular
pathways

1
Kathryn N. Becker * , Mackenzie C. Hagood 2 , Michael Stuckert 2 ,
1
Holly Heck 2 , Krista M. Pettee , Jason Schroeder 3 , and
Kathryn M. Eisenmann 1,2
1 Department of Cell and Cancer Biology, College of Medicine and Life Sciences, University of
Toledo, Toledo, Ohio, United States of America
2 Department of Medical Education, College of Medicine and Life Sciences, University of Toledo,
Toledo, Ohio, United States of America
3 Division of Neurosurgery, Department of Surgery, College of Medicine and Life Sciences, University
of Toledo, Toledo, Ohio, United States of America

Abstract

Glioblastoma (GBM) is the most common and aggressive primary central nervous
system malignancy. Significant resistance to therapeutic intervention is a core feature
of GBM that drives tumor recurrence and underlies the remarkably poor clinical
outcomes associated with this disease. This review explores the therapeutic strategies
and molecular pathways involved in GBM. Therapy resistance in GBM depends on
*Corresponding author: multiple interconnected macrostructural and biomolecular mechanisms, including
Kathryn M. Eisenmann aggressive and diffuse invasion, tumor microtube network formation, stem-like
(kathryn.eisenmann@utoledo.edu) cell enrichment, selective neurovascular permeability, an immunosuppressive
Citation: Becker KN, Hagood MC, microenvironment, and a high degree of inter- and intra-tumoral heterogeneity.
Stuckert M, et al. Targeting Collectively, these pathobiological features insulate specific tumor compartments
glioblastoma invasion and therapy
resistance: Emerging trends and and maintain GBM viability despite significant treatment-induced cellular stress.
molecular pathways. Tumor Discov. While there is enthusiasm for addressing GBM therapeutic resistance, the scale of
2025;4(2):20-41. the challenge remains immense. The identified resistance mechanisms extensively
doi: 10.36922/td.8578
interact and can compensate for single-target assaults. Emerging overlaps between
Received: January 17, 2025 neuro-oncology and developmental neurobiology additionally suggest that GBM
Revised: March 12, 2025 may exploit therapeutic resistance mechanisms yet to be identified, functioning
beyond the current scientific understanding. Thus, the scope and diversity of this
Accepted: March 17, 2025
problem demand a comprehensive therapeutic approach capable of targeting
Published online: April 11, 2025 multiple interacting mechanisms of therapeutic resistance.
Copyright: © 2025 Author(s).
This is an Open-Access article
distributed under the terms of the Keywords: Glioblastoma; Invasion; Tumor microtube; Cytoskeleton
Creative Commons Attribution
License, permitting distribution,
and reproduction in any medium,
provided the original work is
properly cited. 1. Introduction
Publisher’s Note: AccScience Primary central nervous system (CNS) tumors are rare cancers that arise directly from
Publishing remains neutral with cells of the brain or the spinal cord. Tumors that arise from the meningeal tissues
regard to jurisdictional claims in
published maps and institutional are also categorized as primary CNS tumors, and in the United States (US), this
1
affiliations. combined category of tumors represents <1% of cancer diagnoses. Still, these tumors

Volume 4 Issue 2 (2025) 20 doi: 10.36922/td.8578