Table 1.

Summary of existing anti-angiogenic therapeutic strategies and their limitations.

Therapeutic Strategy	Target	Known Therapeutics	Limitations	References
Growth Factor SignalingAMG386	VEGF Family	Bevacizumab, Sorefenib, Sunitinib, Herceptin	• Imbalanced growth factor signaling in tumors • Requirement for targeting multiple growth factors • Narrow therapeutic window between effectiveness and cytotoxicity in off-target sites • Limited access to inhibitor targets due to compromised blood flow, organization of tumor vasculature	4–9 11,17
	TGFβ Family	Lerdelimumab, Metelimumab
	FGF Family	FP-1039, E-3810, TKI258
	Angiopoietin	AMG 386
	EGF	Cetuximab, Panitumumab, Erlotinib
	IGF	NVP-AEW541, NVP-ADW742
Calcium Signaling	NFAT Activation	FK506, Anti-SFRP2 antibody	• Limited access to inhibitor targets due to compromised blood flow	8, 11, 17
Tumor Endothelial Markers	TEM8,SFRP2	Anti-SFRP2 antibody	• Limited access to inhibitor targets due to compromised blood flow • Impaired genome/epigenetic changes to endothelial cell behavior • Abnormal expression of target molecules inhibits drug penetration to interior of tumor – binding site barrier	8, 10, 14, 30
Endogenous angiogenesis inhibitors	Angiostatin	Direct application of the inhibitors, or delivery via original ECM molecules including Collagen IV, Collagen XVIII (Endostatin)	• Narrow therapeutic window between effectiveness and cytotoxicity in off-target sites • Limited access to inhibitor targets due to compromised blood flow • Impaired genome/epigenetic changes to endothelial cell behavior	8,9, 13, 14
	Endostatin
	Thrombospondin-1
	Tumstatin
	Canstatin
	Arrestin
Extracellular Matrix	Matrix Metalloproteinase	MMP9 to release Angiostatin, Endotstatin, Tumstatin	• Narrow therapeutic window between effectiveness and cytotoxicity in off-target sites • Limited access to inhibitor targets due to compromised blood flow, organization of tumor vasculature	9, 14
	integrins αvβ3, αvβ5	Cilengitide, Vitaxin, S247
	Focal adhesion kinase	TAE-226, Pfizer-PF-573,228
Tumor Activated Fibroblasts	Fibroblast Activation Protein	Sibrotuzumab, val-prolineboronic acid	• Small molecule inhibitors ineffective in certain tumor types	8