How to train glioma cells to die: molecular challenges in cell death

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 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. Keywords glioma; apoptosis; autophagy; necrosis; resistance While primary malignant brain tumors are rare, the 5-year survival for these patients is dismal at approximately 10%. Utilizing the World Health Organization based classification, these tumors are categorized as low-grade (I-II) or high-grade malignant gliomas (III-IV) [1]. Specifically, grade IV glioma or glioblastoma (GBM) [2] are the most common and destructive form of malignant glioma. Headaches, seizures, cognitive and personality changes, gait imbalance, sensory loss, and incontinence are common symptoms and can be dependent on the location of the tumor. Symptomatic management for these patients consists mainly of steroids to relieve neurological symptoms associated with edema and Despite aggressive surgical resection and concurrent chemo/radiotherapy 70% of patients diagnosed with GBM will succumb to the disease within two years. A better understanding of the molecular changes in these malignant cells in response to therapy is necessary to unveil how these malignant cells can survive intense chemo/radiation insult. Recent studies have identified numerous mechanisms by which cells "commit suicide" (Fig. 1) and a better understanding of the mechanisms of cell death exploited by different therapeutics is essential for the rational design of future therapeutic strategies. Here we discuss the current treatment strategies utilized to kill GBM cells, and various cell death mechanisms relevant to glioma destruction and resistance. HHS Public Access ApoptosisApoptosis is perhaps the most well studied form of cellular demise consisting of an energydependent cascade of molecular signaling typically involving the cysteine-dependent aspartate-directed proteases called caspases. Caspase-dep...

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