Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and has an exceedingly low median overall survival of only 15 months. Current standard-of-care for GBM consists of gross total surgical resection followed by radiation with concurrent and adjuvant chemotherapy. Temozolomide (TMZ) is the first-choice chemotherapeutic agent in GBM; however, the development of resistance to TMZ often becomes the limiting factor in effective treatment. While O6-methylguanine-DNA methyltransferase repair activity and uniquely resistant populations of glioma stem cells are the most well-known contributors to TMZ resistance, many other molecular mechanisms have come to light in recent years. Key emerging mechanisms include the involvement of other DNA repair systems, aberrant signaling pathways, autophagy, epigenetic modifications, microRNAs, and extracellular vesicle production. This review aims to provide a comprehensive overview of the clinically relevant molecular mechanisms and their extensive interconnections to better inform efforts to combat TMZ resistance.
Highlights
The clinical landscape of glioblastomaGlioblastoma (GBM) is the most common malignant brain tumor in adults, accounting for approximately 15% of all central nervous system tumors and about 45% of primary malignant brain tumors[1]
While studies have shown that it does not improve overall survival in comparison to standard TMZ plus radiotherapy, it has demonstrated utility in quality of life improvement and symptom management . [6,7] Interestingly, a recent study suggests that bevacizumab may affect chemotherapeutic delivery through alteration of perfusion dynamics, suggesting that bevacizumab may play a role in TMZ delivery and preventing resistance[8]
This study revealed that the expression of Snail in GBM resistant cells is modulated by STAT3, which is stimulated by the oversecretion of IL-6[135]
Summary
The clinical landscape of glioblastomaGlioblastoma (GBM) is the most common malignant brain tumor in adults, accounting for approximately 15% of all central nervous system tumors and about 45% of primary malignant brain tumors[1]. Temozolomide (TMZ) has been widely used as the standard chemotherapy for newly-diagnosed GBM since its initial FDA approval in 2005 and the subsequent widespread use of the Stupp regimen[5]. In their landmark paper, Stupp et al.[5] showed that the addition of TMZ chemotherapy to radiation led to a 2-month increase in median overall survival, and this remains one of the most significant enhancements in GBM survival achieved by a novel chemotherapeutic drug to date. While studies have shown that it does not improve overall survival in comparison to standard TMZ plus radiotherapy, it has demonstrated utility in quality of life improvement and symptom management . [6,7] Interestingly, a recent study suggests that bevacizumab may affect chemotherapeutic delivery through alteration of perfusion dynamics, suggesting that bevacizumab may play a role in TMZ delivery and preventing resistance[8]
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