Advances in Targeting the Epidermal Growth Factor Receptor Pathway by Synthetic Products and Its Regulation by Epigenetic Modulators As a Therapy for Glioblastoma

Abstract

Glioma is the most common primary tumor of the nervous system, and approximately 50% of patients exhibit the most aggressive form of the cancer, glioblastoma. The biological function of epidermal growth factor receptor (EGFR) in tumorigenesis and progression has been established in various types of cancers, since it is overexpressed, mutated, or dysregulated. Its overexpression has been shown to be associated with enhanced metastatic potential in glioblastoma, with EGFR at the top of a downstream signaling cascade that controls basic functional properties of glioblastoma cells such as survival, cell proliferation, and migration. Thus, EGFR is considered as an important therapeutic target in glioblastoma. Many anti-EGFR therapies have been investigated both in vivo and in vitro, making their way to clinical studies. However, in clinical trials, the potential efficacy of anti-EGFR therapies is low, primarily because of chemoresistance. Currently, a range of epigenetic drugs including histone deacetylase (HDAC) inhibitors, DNA methylation and histone inhibitors, microRNA, and different types of EGFR inhibitor molecules are being actively investigated in glioblastoma patients as therapeutic strategies. Here, we describe recent knowledge on the signaling pathways mediated by EGFR/EGFR variant III (EGFRvIII) with regard to current therapeutic strategies to target EGFR/EGFRvIII amplified glioblastoma.

The Roles of miRNA in Glioblastoma Tumor Cell Communication: Diplomatic and Aggressive Negotiations

“…Also, TMZ-R GBM cells show an increased expression of Cx43, allowing the formation of connexons for the exchange of miRNAs across GJs [174]. Additionally, EGFR sits at the top of a downstream signaling cascade that controls basic functional properties of GBM cells, such as survival, cell proliferation, and migration [175]. The activation of EGFR leads to downstream signaling pathways such as the phosphorylation of AKT, MAPK, and JNK, also inducing Cx43 expression.…”

Hybrid Quinazoline 1,3,5‐Triazines as Epidermal Growth Factor Receptor (EGFR) Inhibitors with Anticancer Activity: Design, Synthesis, and Computational Study

“…Through their effects on cell proliferation, differentiation, apoptosis, invasion, and angiogenesis, a normal organ development takes place. EGFR signalling in tumour cells, as opposed to normal cells, is changed and often becomes dysregulated, where EGFR is overexpressed and/or obtains a gain‐of‐function mutation [6–11] . This behaviour leads to proliferation of tumour cells where they invade the surrounding tissue.…”

“…EGFR signalling in tumour cells, as opposed to normal cells, is changed and often becomes dysregulated, where EGFR is overexpressed and/or obtains a gain-of-function mutation. [6][7][8][9][10][11] This behaviour leads to proliferation of tumour cells where they invade the surrounding tissue. This results in an increased angiogenesis.…”

Glioblastoma Break-in; Try Something New

“…TMZ in combination with histone deacetylase (HDAC) inhibitors (for example, suberoylan hydroxamic acid, which is a specific inhibitor of HDAC 1, 2, 3, and 6, is currently approved for the treatment of cutaneous T-cell lym-phoma) and chloroquine (chemosensitizing agent) have been tested for various types of cancer, and clinical trials have been conducted to treat glioblastoma. Chloroquine blocks the late stages of the protective cancer cells' reaction-autophagy and promotes apoptosis of the tumor (33,34). HDAC inhibitors promote histone acetylation, which leads to changes in chromatin dynamics; moreover, they favor transcription factor acetylation, which affects gene expression (35).…”