Table 1.

Pre- or Clinical Trials for Targeting Glioblastoma Niches

Tumor niche	Promising therapies	Biological action	Combination strategies	Current status	Pre/clinical effect
Perivascular niche	Bevacizumab	Inhibiting VEGFA	Radiation, temozolomide pembrolizumab	Completed clinical trials	No increase in OS
Hypoxic niche	2ME2	Inhibiting HIF-1α	Temozolomide	Phase I	Modest antitumor effect as a monotherapy, unknown with temozolomide
	PT2977	Inhibiting HIF-2α	N/A	Active, not recruiting (NCT02974738)	N/A
	PT2385	Inhibiting HIF-2α	N/A	Completed clinical trial (NCT03216499)	The results were variable
Invasive niche	RGD	Inhibiting ECM and integrins	N/A	Preclinical	Inhibition of glioma cell migration and anoikis
	TAE226	Inhibiting FAK and IGF-IR	N/A	Preclinical	Prolongation of animal survival
	IS20I	Inhibiting αvβ3	N/A	Preclinical	Inhibition of tumor growth
	Amphotericin B	Reducing microglia	N/A	Preclinical	Prolongation of animal survival
	Targeting WNT5A-GdEC signaling	Promoting existing EC recruitment and GdEC expansion	N/A	Preclinical	Reduction of GBM invasiveness
Immunosuppressive niche	PLX3397	Inhibiting CSF1R	Radiation, temozolomide	Completed clinical trial (NCT01790503)	No improvement of PFS or OS
	BLZ945	Inhibiting CSF1R	Radiation	Preclinical	Significant changes in the dynamics and plasticity of the MDMs and microglia
	Gal3BP mimicking peptide	Disrupting CHI3L1-Gal3 protein binding complex	N/A	Preclinical	Reduction of M2-like MDMs but increased M1-like MDMs and CD8+ T cells
	CAR2BRAIN	Manipulating NK cells	N/A	Active, not recruiting (NCT02974738)	N/A
	Dexamethasone	Anti-inflammatory response	Radiation, temozolomide	Widely used in the clinic	Reduction of tumor-associated edema
GSC Niche	SVZ	Targeting astrocyte-like NSCs at SVZ	Temozolomide	Recruiting (NCT02177578)	N/A
	SVZ	Targeting astrocyte-like NSCs at SVZ	Stereotactic radiosurgery	Active, not recruiting, (NCT03956706)	N/A
	DC vaccination	Autologous DCs loaded with autogeneic GSCs (A2B5+)	Radiation, temozolomide	Recruiting, (NCT01567202)	N/A
	DC vaccination	Autologous DCs loaded with autologous tumor-associated antigens	Radiation, temozolomide	Active, not recruiting, (NCT03400917)	N/A
	DEN-STEM	DC immunotherapy against GSCs	Temozolomide	Recruiting, (NCT03548571)	N/A
	SurVaxM vaccine therapy	Targeting survivin-expressed GSCs	Temozolomide	Active, not recruiting, (NCT02455557)	N/A
	IL13Rα2 CAR-T cell therapy	Target GSCs based on IL13Rα2 expression	Ipilimumab nivolumab	Recruiting, (NCT04003649)	N/A

2ME2, 2-methoxyestradiol; CAR, chimeric antigen receptor; CHI3L1, chitinase-3-like 1; CSF1R, colony-stimulating factor 1 receptor; DC, dendritic cell; EC, endothelial cell; ECM, extracellular matrix; FAK, focal adhesion kinase; Gal3, galectin-3; Gal3BP, galectin-3 binding protein; GBM, glioblastoma; GdEC, GSC-derived endothelial-like cell; GSC, glioblastoma stem cell; HIF, hypoxia-inducible factor; MDM, myeloid-derived macrophage; N/A, not application; NK, natural killer; NSC, neural stem cell; OS, overall survival; PFS, progression-free survival; RGD, Arg-Gly-Asp; SVZ, subventricular zone.