Molecular Pathways and Genomic Landscape of Glioblastoma Stem Cells: Opportunities for Targeted Therapy

Abstract

Glioblastoma (GBM) is an aggressive tumor of the central nervous system categorized by the World Health Organization as a Grade 4 astrocytoma. Despite treatment with surgical resection, adjuvant chemotherapy, and radiation therapy, outcomes remain poor, with a median survival of only 14-16 months. Although tumor regression is often observed initially after treatment, long-term recurrence or progression invariably occurs. Tumor growth, invasion, and recurrence is mediated by a unique population of glioblastoma stem cells (GSCs). Their high mutation rate and dysregulated transcriptional landscape augment their resistance to conventional chemotherapy and radiation therapy, explaining the poor outcomes observed in patients. Consequently, GSCs have emerged as targets of interest in new treatment paradigms. Here, we review the unique properties of GSCs, including their interactions with the hypoxic microenvironment that drives their proliferation. We discuss vital signaling pathways in GSCs that mediate stemness, self-renewal, proliferation, and invasion, including the Notch, epidermal growth factor receptor, phosphatidylinositol 3-kinase/Akt, sonic hedgehog, transforming growth factor beta, Wnt, signal transducer and activator of transcription 3, and inhibitors of differentiation pathways. We also review epigenomic changes in GSCs that influence their transcriptional state, including DNA methylation, histone methylation and acetylation, and miRNA expression. The constituent molecular components of the signaling pathways and epigenomic regulators represent potential sites for targeted therapy, and representative examples of inhibitory molecules and pharmaceuticals are discussed. Continued investigation into the molecular pathways of GSCs and candidate therapeutics is needed to discover new effective treatments for GBM and improve survival.

Keywords: glioblastoma; molecular pathway; stem cell; targeted therapy.

Figure 1

Sonic hedgehog signaling pathway. In the absence of hedgehog ligand, Ptch inhibits Smo, resulting in formation of Gli repressor that inhibits target genes. Ptch and SUFU function as tumor suppressors. Hedgehog ligand’s interaction with Ptch results in its degradation, allowing a signaling cascade mediated by Smo that forms GliA. This transcription factor activates genes associated with tumor proliferation. Inhibitors of Smo represent a potential therapeutic target against GSCs. GliA—Gli activator, GliR—gli repressor, HH—hedgehog ligand, Ptch—Patched, Smo—smoothened, SUFU—Suppressor of fused homolog.

Figure 2

STAT3 signaling pathway. The IL-6 cytokine triggers dimerization and activation of the IL6 receptor with its gp130 subunit. JAK phosphorylation in turn results in STAT3 phosphorylation, which dimerizes and translocates to the nucleus to upregulate target genes associated with stemness and GSC survival. Inhibition of the STAT3 pathway can be achieved at several points, including targeting of receptor signaling using WP1066 or bazedoxifene and inhibition of STAT3 dimerization and signaling using Stattic, STA-21, or S31-201. GP130—glycoprotein 130, IL6R—IL6 receptor, P—phosphorylation, STAT3—signal transducer and activator of transcription 3.

Figure 3

Proposed future management algorithm for GBM. The genomic revolution has offered significant insights into pathogenesis of GBM and resistance to TMZ and RT. Clinicians may eventually have an array of pharmaceutical agents and therapeutics designed to target specific molecular components of tumor cells and GSCs. Following maximal surgical resection, genomic analysis should be performed to identify key signaling pathways and genomic mutations in GSCs that can allow for personalized targeted therapy, performed alongside adjuvant TMZ and RT. Clinicians may eventually select from amongst several drugs those likely to exert the most profound anti-GBM effect based on the genomic analysis. In the case of tumor progression or recurrence, repeat sequencing can be performed to identify new actionable mutations for targeted therapy. Additionally, the targeted therapy may sensitize the tumors to TMZ and RT, and synergistic effects may arise from multiple regimens. Additional therapeutic agents can also be designed to target differentiated tumor cells. EGFR—epidermal growth factor receptor, EZH2—Enhancer of zeste homolog 2, GBM—glioblastoma, HDAC—histone deacetylase, HIF—hypoxia inducible factor, ID-1—Inhibitor of differentiation-1, mTOR—mammalian target of rapamycin, PI3K—Phosphoinositide 3-kinase, RT—radiation therapy, Shh—sonic hedgehog, STAT3—Signal Transducer and Activator Of Transcription 3, TMZ—temozolomide, VEGF—vascular endothelial growth factor.