The overall goal of the Sanderson Lab is to determine the role of the heparan sulfate / heparanase axis in regulating cancer and to use this knowledge to develop new anti-cancer therapies. The immediate goal of this project is to design and develop novel heparanase inhibitors to treat multiple myeloma. Heparanase, an endoglycosidase that cleaves heparan sulfate chains, is upregulated in many types of cancers and promotes an aggressive tumor phenotype. Heparanase is present in the bone marrow of many myeloma patients where high levels of the enzyme correlate with enhanced angiogenesis and poor prognosis. Using in vivo models, we have also shown that heparanase is a key driver of myeloma growth, osteolysis and metastasis. Together, these studies identify heparanase as a viable target for myeloma therapy and support our hypothesis that inhibitors of heparanase will block myeloma tumor growth and progression. In preliminary proof-of-principle studies, we have synthesized a chemically modified, non-anticoagulant heparin that acts as a potent inhibitor of heparanase activity in vitro and myeloma tumor growth in vivo. The goal of this project is to generate novel oligosaccharide and antibody inhibitors of heparanase that have characteristics favorable for their development as anti-myeloma drugs. To accomplish this we have assembled an interdisciplinary team of senior scientists having expertise in carbohydrate chemistry (Ronzoni Institute, Milan), heparanase biology and enzymology (Technion, Haifa), heparan sulfate/heparanase function in myeloma (UAB) and pharmacology and drug development (Ohio State).
Aim 1 focuses on rational design of oligosaccharide inhibitors of heparanase enzyme activity;
Aim 2 focuses on heparanase structural and molecular modeling studies that will enhance rational design of oligosaccharide inhibitors;
Aim 3, using in vivo models of myeloma, will test the characteristics and efficacy of drug candidates developed in aim 1 with the goal of moving the most efficacious compounds toward clinical trials. These studies have potential for high impact by delivering new therapeutics for myeloma and perhaps other cancers and by providing new structural information on heparanase that will help unravel the mechanism of action of this important enzyme.
Heparanase is a protein made by cancer cells that plays a major role in helping them grow and spread throughout the body. This project is designed to develop new drugs that will block the function of heparanase and thereby block tumor growth and metastasis.
|Ramani, Vishnu C; Zhan, Fenghuang; He, Jianbo et al. (2016) Targeting heparanase overcomes chemoresistance and diminishes relapse in myeloma. Oncotarget 7:1598-607|
|Ramani, Vishnu C; Vlodavsky, Israel; Ng, Mary et al. (2016) Chemotherapy induces expression and release of heparanase leading to changes associated with an aggressive tumor phenotype. Matrix Biol 55:22-34|
|Theocharis, Achilleas D; Skandalis, Spyros S; Neill, Thomas et al. (2015) Insights into the key roles of proteoglycans in breast cancer biology and translational medicine. Biochim Biophys Acta 1855:276-300|
|Casu, Benito; Naggi, Annamaria; Torri, Giangiacomo (2015) Re-visiting the structure of heparin. Carbohydr Res 403:60-8|
|Alekseeva, Anna; Casu, Benito; Cassinelli, Giuseppe et al. (2014) Structural features of glycol-split low-molecular-weight heparins and their heparin lyase generated fragments. Anal Bioanal Chem 406:249-65|
|Coletti, Alessia; Elli, Stefano; Macchi, Eleonora et al. (2014) Conformational changes of 1-4-glucopyranosyl residues of a sulfated C-C linked hexasaccharide. Carbohydr Res 389:134-40|
|Alekseeva, Anna; Elli, Stefano; Cosentino, Cesare et al. (2014) Susceptibility of enoxaparin reducing end amino sugars to periodate oxidation. Carbohydr Res 400:33-43|
|Ramani, Vishnu C; Purushothaman, Anurag; Stewart, Mark D et al. (2013) The heparanase/syndecan-1 axis in cancer: mechanisms and therapies. FEBS J 280:2294-306|
|Vlodavsky, Israel; Blich, Miry; Li, Jin-Ping et al. (2013) Involvement of heparanase in atherosclerosis and other vessel wall pathologies. Matrix Biol 32:241-51|
|Langeslay, Derek J; Urso, Elena; Gardini, Cristina et al. (2013) Reversed-phase ion-pair ultra-high-performance-liquid chromatography-mass spectrometry for fingerprinting low-molecular-weight heparins. J Chromatogr A 1292:201-10|
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