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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138535-03
Application #
8204594
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Forry, Suzanne L
Project Start
2010-02-01
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$403,257
Indirect Cost
$62,260
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Alekseeva, Anna; Casu, Benito; Torri, Giangiacomo et al. (2013) Profiling glycol-split heparins by high-performance liquid chromatography/mass spectrometry analysis of their heparinase-generated oligosaccharides. Anal Biochem 434:112-22
Ritchie, Joseph P; Ramani, Vishnu C; Ren, Yongsheng et al. (2011) SST0001, a chemically modified heparin, inhibits myeloma growth and angiogenesis via disruption of the heparanase/syndecan-1 axis. Clin Cancer Res 17:1382-93
Borsig, Lubor; Vlodavsky, Israel; Ishai-Michaeli, Rivka et al. (2011) Sulfated hexasaccharides attenuate metastasis by inhibition of P-selectin and heparanase. Neoplasia 13:445-52

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