All ETDs from UAB

Advisory Committee Chair

Ralph D Sanderson

Advisory Committee Members

Kevin Harris

Martin Johnson

Yongsheng Ren

Danny Welch

Yang Yang

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Heparanase, an endoglycosidase which cleaves heparan sulfate chains at specific sites, is rarely expressed in normal tissues but becomes evident in many human cancers. We have previously shown that heparanase promotes myeloma growth and angiogenesis through modulation of the tumor microenvironment. Recognition that heparanase drives the aggressive myeloma phenotype has led to new strategies designed to therapeutically target this enzyme. SST0001, a non-anticoagulant heparin that is 100% N-acetylated and 25% glycol split, was previously described as a potent inhibitor of heparanase activity in vitro, and, in limited in vivo experiments, SST0001 was identified to have efficacy as an anti-tumor agent in models of myeloma and melanoma. We now report that SST0001 can effectively inhibit myeloma growth in vivo, even when confronted with an aggres-sively growing tumor within human bone. Importantly, we find that SST0001 treatment of tumor bearing animals or myeloma cells in vitro causes changes within tumors consis-tent with the compound's ability to inhibit heparanase. This includes inhibition of ex-pression of HGF, VEGF and MMP-9 accompanied by suppressed angiogenesis. In addi-tion, SST0001 diminishes shedding of syndecan-1, a heparan sulfate proteoglycan previ-ously shown to be a potent promoter of myeloma growth. SST0001 also inhibited the heparanase-mediated degradation of syndecan-1 heparan sulfate chains thus confirming the anti-heparanase activity of this compound. When used in combination with dexa-methasone, a conventional anti-myeloma agent, SST0001 blocked tumor growth in vivo presumably through dual targeting of the tumor and its microenvironment. These results provide mechanistic insight into the anti-tumor action of SST0001 and further validate its use as a therapeutic tool for treating multiple myeloma. As the role of heparanase in driv-ing other diseases becomes evident, the impact of a successfully translated heparanase inhibitor will have significant clinical impact, far beyond multiple myeloma and cancer, in improving survival and quality of life for those patients afflicted with diseases exacer-bated by this enzyme.

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