Targeting Aggressive Cancer Stem Cells in Glioblastoma

Abstract

Glioblastoma (GBM) is the most common and fatal type of primary brain tumor. Gliosarcoma (GSM) is a rarer and more aggressive variant of GBM that has recently been considered a potentially different disease. Current clinical treatment for both GBM and GSM includes maximal surgical resection followed by post-operative radiotherapy and concomitant and adjuvant chemotherapy. Despite recent advances in treating other solid tumors, treatment for GBM and GSM still remains palliative, with a very poor prognosis and a median survival rate of 12–15 months. Treatment failure is a result of a number of causes, including resistance to radiotherapy and chemotherapy. Recent research has applied the cancer stem cells theory of carcinogenesis to these tumors, suggesting the existence of a small subpopulation of glioma stem-like cells (GSCs) within these tumors. GSCs are thought to contribute to tumor progression, treatment resistance, and tumor recapitulation post-treatment and have become the focus of novel therapy strategies. Their isolation and investigation suggest that GSCs share critical signaling pathways with normal embryonic and somatic stem cells, but with distinct alterations. Research must focus on identifying these variations as they may present novel therapeutic targets. Targeting pluripotency transcription factors, SOX2, OCT4, and Nanog homeobox, demonstrates promising therapeutic potential that if applied in isolation or together with current treatments may improve overall survival, reduce tumor relapse, and achieve a cure for these patients.

Downregulation of lncRNA-HOXA11-AS modulates proliferation and stemness in Glioma cells

“…(*p < 0.05; **p < 0.01; ***p < 0.001) via protein microarray. Previous studies have demonstrated that the Oct4, Sox2, Sox17, and Nanog are the important regulator of stemness in the different types of cancer including GBM [16,17]. In summary, our findings further indicate that HOXA11-AS maybe involve in maintenance of stemness in glioma.…”

HOXA11 antisense long noncoding RNA (HOXA11‐AS): A promising lncRNA in human cancers

“…The only treatment option for GBM is aggressive surgical resections because it is resistant to radiotherapy as well as chemotherapy. Regardless of latest advances in treating GBM, treatments for GBM remain palliative and do slight to modify the poor prognosis due to this cancer 32. The prognosis for GBM is very poor, with a mean survival of 12‐18 months.…”

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

“…Increasing evidence suggests that the genetic, epigenetic, and signaling heterogeneity of GBM underlies the ineffectiveness of currently available therapeutics (1,2). Additionally, therapeutic schemes devised to challenge brain tumor cells are frequently thwarted by insufficient delivery caused by pharmacokinetics, the blood-brain barrier (BBB), and an altered tumor microenvironment in which tumor-derived signaling recruits immunomodulatory cells and induces extracellular matrix remodeling to build safe harbors of tumorigenic niches (3)(4)(5). These obstacles call for tailored therapeutic strategies to counter tumor heterogeneity and overcome roadblocks in delivery.…”

“…RNAi targeting drivers of tumorigenesis shows strong potential to supplement the development of traditional small-molecule pharmaceutics (6). However, delivery remains a key obstacle for efficient RNAi against tumor drivers (5,7,8). RNA-sequencing analysis of patient tissue combined with histology and in situ hybridization (Ivy Glioblastoma Atlas Project; SI Appendix, Fig.…”