Heparanase is recognized as a master regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients and a prime target for therapy. Although carbohydrate-based heparanase have been developed, but none were translated into use in the clinic. Additionally, interaction of heparanase with heparan sulfate (HS) is regulated by substrate sulfation sequences, and only substrates with specific sulfation patterns are cleaved by heparanase. Although the crystal structure of human heparanase has been recently resolved, it still does not allow determination of the structure of binding epitopes with defined N-and O- sulfation patterns at each subsite of heparanase. To address these challenges, Aim 1 entails a new modular chemical approach for the parallel combinatorial synthesis of a library of HS trisaccharide substrates, representing all possible N-acetyl as well as O- and N-sulfation motifs. Our strategy provides a systematic understanding of substrate specificity for heparanase and how heparanase selects favorable cleavage site.
In Aim 2, we propose to develop heparanase- inhibiting sulfated oligosaccharides of high efficacy and clinical applicability.
In Aim 3, the most potent inhibitors developed in Aim 2 will be tested for cross-bioactivity to other HS-binding proteins, which are responsible for mediating anticoagulant and angiogenic activity, antibody- induced thrombocytopenia, and tumor cell metastasis. With the ultimate goal of understanding if the in vitro inhibition of heparanase would translate in vivo, we will evaluate the effectiveness of the most potent inhibitor(s) in inhibiting lymphoma tumor growth and experimental metastasis. Together, this project will provide insight into sulfate-recognition motifs and favorable cleavage site for use to develop inhibitors of heparanase. The significant impact of this project is that, if successful, it could lead to the discovery of a heparanase-inhibiting small carbohydrate molecule for treatment of lymphomas, which are the fifth leading cancer in the North America, produce tumors predominantly in lymphoid structures.
Heparanase is recognized as a master regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients and a prime target for therapy. Although carbohydrate-based heparanase have been developed, but none were translated into use in the clinic. The goal of the proposal is to combine organic chemistry and tumor biology for the development of heparanase-inhibiting sulfated oligosaccharides of high efficacy and clinical applicability that could lead to the discovery of anti-cancer drug for treatment of lymphomas, the fifth leading cancer in the North America.
