Table 1.

Potential therapeutic targets against cancer stem cells.

Cancer Stem Cell Pathway	Potential Therapeutic Target	Agents	Effects	Target Model	References
Notch pathway	Notch signaling	Notch-1 siRNA, Delta-like-1 siRNA, Jagged-1 siRNA, Delta-like-1 Fusion protein	Downregulation of Notch and its ligands leads to a reduction of oncogenic potential of GSCs	GBM cell lines	[80,81]
	Notch signaling	γ-secretase inhibitor GSI-18	Inhibition of Notch by GSIs increases neuronal differentiation and decreases tumorigenicity	DAOY, PFSK, D283Med, and D425Med cell lines. HSR-GBM1 and JHH520 GBM neurosphere lines	[82,83]
		MRK003
	Notch + autophagy targeting	MRK003 + chloroquine	Protective autophagy abrogated by combination with chloroquine	HSR-GBM1 and JHH520 GBM neurosphere lines	[83]
	Notch + leptin	GSIs + LFDI peptide (Leu-Asp-Phe-Ile)	High expression of leptin receptors in tumorspheres from GBM	human fetal glial cells SVG p12, human	[86]
				GBM cell lines
				U-87 MG, T98G
	Hypoxic tumor cells	vasorin	Vasorin acts triggering Notch under hypoxic conditions	GSCs and non-GSCs from GBM	[87]
Shh pathway	Shh	cyclopamine	Inhibition of hedgehog pathway by cyclopamine inhibited formation of GBM-derived neurospheres	40–60% reduction in the growth of adherent glioma lines	[91]
Wnt pathway	GBM differentiation pathway	Dickkopf-1 (DKK1) Wnt inhibitor suppress PLAGL2	PLAGL2 acts as an oncogene in human GBM regulating Wnt signaling	primary GBM and established glioma cell lines	[92]
	ASCL1	-	ASCL1 and Wnt signaling are connected and collaborate with developmental transcription factors (TFs). They support GSCs’ growth	GSC lines derived from different human tumors	[93]
	RYK pathway	-	RYK promotes stem cell-like and tumorigenic features to glioma cells and are essential to support GSCs	GBM cell line U87MG, AM38, and U251MG cells	[94]
	Wnt/β catenin	-	Tumor chemoresistance acquisition depends on mesenchymal transformation that is triggered by Wnt/β catenin signaling	GSCs	[93]
Tumor microenvironment	Microvasculature and TAMs	Erlotinib and Bevacizumab	Bevacizumab treatment reduces the number of CD133+/Nestin+ tumor initiation cells and decreases microvasculature density and tumor growth	CSCs obtained from tumors	[95]
	M2-TAMs and microvasculature	BLZ945-Inhibitor of the CSF-1 receptor (CSF-1R)	TAMs support GBM tumor growth by promoting neovascularization. They play a tumor-supportive role in GBM progression	Proneural GBM	[96]
	TAMs	shPOSTN	Silencing POSTN that recruits TAMS reduces TAM density, inhibits tumor growth, and increases survival of mice bearing GSC-derived xenografts	Human GBM specimens and glioma-derived cells	[97]