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Updated: Oct 2, 2025
Digital Spatial Profiling for Characterization of the Microenvironment in Adult-Type Diffusely Infiltrating Glioma
Published on: September 13, 2022
Therapeutic Opportunities of Disrupting Genome Integrity in Adult Diffuse Glioma
Diana Aguilar-Morante1, Daniel Gómez-Cabello1, Hazel Quek2
1Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain.
Abstract:
Adult diffuse glioma, particularly glioblastoma (GBM), is a devastating tumor of the central nervous system. The existential threat of this disease requires on-going treatment to counteract tumor progression. The present outcome is discouraging as most patients will succumb to this disease. The low cure rate is consistent with the failure of first-line therapy, radiation and temozolomide (TMZ). Even with their therapeutic mechanism of action to incur lethal DNA lesions, tumor growth remains undeterred. Delivering additional treatments only delays the inescapable development of therapeutic tolerance and disease recurrence. The urgency of establishing lifelong tumor control needs to be re-examined with a greater focus on eliminating resistance. Early genomic and transcriptome studies suggest each tumor subtype possesses a unique molecular network to safeguard genome integrity. Subsequent seminal work on post-therapy tumor progression sheds light on the involvement of DNA repair as the causative contributor for hypermutation and therapeutic failure. In this review, we will provide an overview of known molecular factors that influence the engagement of different DNA repair pathways, including targetable vulnerabilities, which can be exploited for clinical benefit with the use of specific inhibitors.
Insights
Glioblastoma (GBM) treatment fails due to DNA repair mechanisms that cause resistance. Targeting these DNA repair pathways offers a promising strategy for lifelong tumor control in brain tumors.
Area of Science:
- Neuro-oncology
- Cancer genomics
- Molecular biology
Background:
- Adult diffuse gliomas, especially glioblastoma (GBM), are aggressive central nervous system tumors with poor prognoses.
- Current first-line therapies, including radiation and temozolomide (TMZ), often fail due to therapeutic resistance and disease recurrence.
- Tumor progression despite treatment highlights the need to understand and overcome resistance mechanisms.
Purpose of the Study:
- To review molecular factors influencing DNA repair pathways in glioblastoma.
- To identify targetable vulnerabilities within these pathways for improved clinical outcomes.
- To re-examine strategies for achieving lifelong tumor control by addressing therapeutic resistance.
Main Methods:
- Review of genomic and transcriptome studies on adult diffuse glioma.
- Analysis of seminal research on post-therapy tumor progression and DNA repair.
- Identification of molecular factors and pathways involved in therapeutic resistance.
Main Results:
- Genomic and transcriptome studies reveal unique molecular networks for genome integrity in glioma subtypes.
- DNA repair pathways are implicated as a major cause of hypermutation and therapeutic failure.
- Specific molecular factors influence the engagement of various DNA repair pathways.
Conclusions:
- Understanding DNA repair mechanisms is crucial for overcoming therapeutic resistance in glioblastoma.
- Targetable vulnerabilities exist within DNA repair pathways that can be exploited for clinical benefit.
- Developing inhibitors targeting these pathways may lead to more effective and durable treatments for brain tumors.
