Mechanisms, Microenvironments, and Models: Understanding Therapeutic Resistance in Glioblastoma

Area of Science:

• Neuro-oncology
• Cancer Biology
• Immunology

Background:

• Glioblastoma (GBM) is the most lethal primary brain tumor, with median survival around 16 months despite aggressive multimodal therapy.
• Therapeutic resistance is a hallmark of GBM, leading to tumor recurrence and poor outcomes.
• Understanding resistance mechanisms is crucial for developing effective treatments.

Purpose of the Study:

• To synthesize current understanding of molecular, cellular, and anatomical determinants of resistance to various therapies in adult GBM.
• To critically evaluate preclinical models for their ability to recapitulate GBM resistance.
• To outline emerging strategies to overcome therapeutic resistance in GBM.

Main Methods:

• Comprehensive review of existing literature on GBM therapeutic resistance.
• Analysis of molecular and cellular mechanisms driving resistance.
• Evaluation of preclinical models (cell lines, xenografts, GEMMs).

Main Results:

• GBM resistance is driven by tumor-intrinsic factors (heterogeneity, plasticity) and microenvironmental constraints.
• Key resistance mechanisms include DNA damage response activation, hypoxic adaptation, mesenchymal transition, and immune evasion.
• Current preclinical models have limitations in fully replicating human GBM resistance.

Conclusions:

• Overcoming GBM resistance requires addressing heterogeneity, plasticity, and the immunosuppressive tumor microenvironment.
• Improved preclinical models and combination therapies are essential for therapeutic advancement.
• Developing novel strategies, including biomarker-driven approaches, is critical for durable GBM treatment.