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How to train glioma cells to die: molecular challenges in cell death
Jeffrey Wojton1,2, Walter Hans Meisen1, Balveen Kaur3
1Department of Neurological Surgery, The Ohio State University Medical Center, 385-B OSUCCC, 410 West 12th Avenue, Columbus, OH, 43210, USA.
Abstract:
The five-year survival rate for patients with malignant glioma is less than 10%. Despite aggressive chemo/radiotherapy these tumors have remained resistant to almost every interventional strategy evaluated in patients. Resistance to these agents is attributed to extrinsic mechanisms such as the tumor microenvironment, poor drug penetration, and tumoral heterogeneity. In addition, genetic and molecular examination of these tumors has revealed defective apoptotic regulation, enhanced pro-survival autophagy signaling, and a propensity for necrosis that aids in the adaptation to environmental stress and resistance to treatment. The combination of extrinsic and intrinsic hallmarks in glioma contributes to the multifaceted resistance to traditional anti-tumor agents. Here we describe the biology of the disease relevant to therapeutic resistance, with a specific focus on molecular deregulation of cell death pathways. Emerging studies investigating the targeting of these pathways including BH3 mimetics and autophagy inhibitors that are being evaluated in both the preclinical and clinical settings are discussed. This review highlights the pathways exploited by glioblastoma cells that drive their hallmark pro-survival predisposition and makes therapy development such a challenge.
Insights
Malignant glioma, a deadly brain cancer, resists treatment due to tumor environment and cell survival mechanisms. New therapies targeting cell death pathways offer hope for overcoming this resistance.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Molecular Therapeutics
Background:
- Malignant glioma exhibits a dismal <10% five-year survival rate.
- Current chemo/radiotherapy strategies show limited efficacy due to intrinsic and extrinsic resistance mechanisms.
Purpose of the Study:
- To review the biological basis of therapeutic resistance in malignant glioma.
- To focus on the molecular deregulation of cell death pathways and emerging therapeutic strategies.
Main Methods:
- Review of existing literature on glioma biology, therapeutic resistance, and molecular pathways.
- Analysis of genetic and molecular characteristics contributing to treatment failure.
- Discussion of preclinical and clinical studies on novel therapeutic agents.
Main Results:
- Glioma resistance is driven by extrinsic factors (microenvironment, drug penetration, heterogeneity) and intrinsic factors (defective apoptosis, enhanced autophagy, necrosis).
- Molecular deregulation of cell death pathways is a key hallmark of glioblastoma.
- Emerging therapies like BH3 mimetics and autophagy inhibitors show potential.
Conclusions:
- Understanding the multifaceted resistance mechanisms in glioma is crucial for developing effective treatments.
- Targeting pro-survival pathways offers a promising avenue for future glioblastoma therapy development.