Abstract 1004: LHT7, a heparin-taurocholate conjugate, inhibits multiple stages of angiogenesis by targeting VEGF, FGF2 and PDGF-B
Authors: Chung Seung Woo , Choi Jeong U. , Kim Sang Yoon , Byun Youngro 
Published: May 2015

Angiogenesis is a critical process in tumor progression and metastasis. Therefore, many angiogenesis inhibitors have been developed as cancer therapeutics, especially targeting vascular endothelial growth factor (VEGF) signaling pathway. These VEGF blockers effectively inhibited the tumor growth initially, but failed to produce enduring clinical response due to occurrence of acquired resistance. Mechanism of the resistance is not clearly understood so far. However, many studies have reported an upregulation of alternative angiogenic pathways when VEGF was blocked that led to recurrence of tumor angiogenesis. Other studies suggested that stabilization of endothelium by mural cells is also responsible for the resistance. Therefore, simultaneous inhibition of the several angiogenic pathways that are involved in multiple stages of angiogenesis would potentially overcome this limitation.

To develop such an angiogenesis inhibitor, we regarded heparin as a lead compound, since wide-array of pro-angiogenic factors are heparin-binding proteins. We have previously reported a heparin-derived angiogenesis inhibitor, LHT7, which blocks VEGF signaling pathway and inhibit tumor angiogenesis. In this study, we show that LHT7 could block fibroblast growth factor 2 (FGF2) and platelet-derived growth factor B (PDGF-B) signaling pathway as well as VEGF. We prepared a set of in vitro studies that represent each step of the initial robust angiogenesis, including endothelial cell migration, angiogenic sprouting from pre-existing vasculatures and endothelial cell differentiation. An in vitro experiment that mimic the maturation of endothelium was also carried out. The inhibitory effect of LHT7 on VEGF, FGF2 and PDGF-B at the molecular level was studied by determining the phosphotyrosine level of the corresponding receptors. The effect was further assessed in vivo by using matrigel plug assay. All the results indicated that LHT7 blocked VEGF, FGF2 and PDGF-B, leading to inhibition of multiple stages of angiogenic process in terms of initial angiogenic response and maturation of endothelium. In addition, numbers of studies have reported vascular normalization during treatment of VEGF blockers, which is closely related to vascular maturation. However, dynamic contrast-enhanced magnetic resonance imaging of LHT7-treated tumor-bearing animals did not show any sign of vascular normalization and directly lead to decreased perfusion of blood throughout the tumor.

Our results show that LHT7 could effectively inhibit tumor angiogenesis by blocking multiple stages of angiogenesis and potentially overcome the acquired resistance against angiogenesis inhibitors. Furthermore, they imply that heparin could be an excellent lead compound to develop a multi-targeted angiogenesis inhibitor.

Citation Format: Seung Woo Chung, Jeong Uk Choi, Sang Yoon Kim, Youngro Byun. LHT7, a heparin-taurocholate conjugate, inhibits multiple stages of angiogenesis by targeting VEGF, FGF2 and PDGF-B. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1004. doi:10.1158/1538-7445.AM2014-1004