Table 3.

Outlook

Pathways or targets	Limitations	Hotspots
EGFR	EGFR inhibitors or antibody appear inactive, partly due to the existence of BBB	Target on EGFR amplification and EGFRvIII
PI3K/AKT/mTOR	Most of the drugs experience poorly tolerance, and the regulation of this pathway is far too complex	combine PI3K/SKT/mTOR inhibitors with other drugs
MET	There is still no effective kind of drugs	Combination of c-MET inhibitor and PI3K inhibitors due to their cooperation to drug resistance
FGFR	Population of patients that could gain benefit from this target is extraordinarily small
BRAF	Mutations of this target are rare	BRAFv600E in GBM needs to be further studied
NTRK	The incidence of NTRK gene fusion seems to be very low in glioblastoma	NTRK fusion as a therapeutic target is active and molecular heterogeneity screening in the diagnosis of GBM is significant
pRB	Regulation of cell cycle and apoptosis is complex
P53	Effort on promoting the refolding of mutant proteins into wild-type conformations meets failure	Inhibitors of MDM2/4 and Weel kinase
TERT	Though TERT mutation is commonly identified in GBM, it has not yet become the main pharmacological target for tumor therapy	Novel inhibitors need to be developed
proteasome
TGF-β	The function of TGF β protein family is complex and the regulatory pathways are widely crossed	Combine TMA and TGF inhibitors
PD-1		Combine PD-1 and other immunotherapy target
LAG-3	there are few trials about LAG-3 inhibitors or antibodies involved in GBM therapy
CTLA-4		CTLA-4 inhibitors combined with TMZ, anti-PD-1 or other drugs appear promising
IDO1		Enzymatic and non-enzymatic activity of IDO
CD73 and CD39		In tumor microenvironment, both CD73 and CD39 participate in regulation of ATP-adenosine axis
CD27-CD70		Combination of CD27 agonist and CD70 inhibitor
CD276	Un-defined isoforms and intracellular domain with unknown ligand	CD276 is correlated with angiogenesis
CD47	Polymorphism of SIRPα, ligand of CD47	Anti-CD47 promotes phagocytosis of glioma