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 define heparanase regulation of the metastatic cascade using multiple myeloma as a model cancer. Myeloma is a devastating cancer that thrives in the bone marrow and disseminates throughout the skeleton leading to severe pain, poor quality of life and eventual death of the patient. Although it is the metastatic nature of this cancer that kills patients, unfortunately, the mechanisms regulating metastasis in myeloma are unknown. The key to improving patient treatment lies in developing a mechanistic understanding of myeloma metastasis and testing new inhibitors to block tumor dissemination. Using in vivo models, we have shown that the heparan sulfate degrading enzyme heparanase is a key driver of myeloma growth, angiogenesis, osteolysis and metastasis. Importantly, we also discovered that enzymatically active heparanase is present within the bone marrow of myeloma patients and it correlates with poor patient prognosis. Striking new data from our lab indicates that heparanase acts as a master regulator of metastasis in myeloma by upregulating expression of several genes including VEGF, MMP-9 and uPA/uPAR that work in concert to drive metastasis. We hypothesize that heparanase acts as a key mediator of myeloma metastasis by promoting initial intravasation of tumor cells into the blood at the primary tumor site and by preparing pre-metastatic niches in bone that facilitate tumor cell homing and growth. Given these two critical functions in metastasis, we further hypothesize that heparanase inhibitors in combination with other anti-myeloma compounds will provide a novel and potent therapeutic approach to this deadly disease.
Aim 1 will examine the importance of heparanase in driving myeloma metastasis, the stage(s) of metastasis where heparanase exerts its effects and the influence of heparanase on establishing pre-metastatic niches in the bone marrow.
Aim 2 will test a novel heparanase inhibitor in for its anti- metastatic effects in vivo when administered either as a single agent or in combination with dexamethasone.

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 reveal how heparanase functions and to test a new anti- heparanase drug to determine if it can block the spread of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138340-05
Application #
8464021
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
2009-07-03
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$308,263
Indirect Cost
$97,845
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Beauvais, DeannaLee M; Jung, Oisun; Yang, Yang et al. (2016) Syndecan-1 (CD138) Suppresses Apoptosis in Multiple Myeloma by Activating IGF1 Receptor: Prevention by SynstatinIGF1R Inhibits Tumor Growth. Cancer Res 76:4981-93
Jung, O; Trapp-Stamborski, V; Purushothaman, A et al. (2016) Heparanase-induced shedding of syndecan-1/CD138 in myeloma and endothelial cells activates VEGFR2 and an invasive phenotype: prevention by novel synstatins. Oncogenesis 5:e202
Sanderson, Ralph D; Elkin, Michael; Rapraeger, Alan C et al. (2016) Heparanase regulation of cancer, autophagy and inflammation: New mechanisms and targets for therapy. FEBS J :
Ramani, Vishnu C; Zhan, Fenghuang; He, Jianbo et al. (2016) Targeting heparanase overcomes chemoresistance and diminishes relapse in myeloma. Oncotarget 7:1598-607
Purushothaman, Anurag; Bandari, Shyam Kumar; Liu, Jian et al. (2016) Fibronectin on the Surface of Myeloma Cell-derived Exosomes Mediates Exosome-Cell Interactions. J Biol Chem 291:1652-63
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
VanValkenburg, MaryAnn E; Pruitt, Gwendolyn I; Brill, Ilene K et al. (2016) Family history of hematologic malignancies and risk of multiple myeloma: differences by race and clinical features. Cancer Causes Control 27:81-91
Stewart, Mark D; Ramani, Vishnu C; Sanderson, Ralph D (2015) Shed syndecan-1 translocates to the nucleus of cells delivering growth factors and inhibiting histone acetylation: a novel mechanism of tumor-host cross-talk. J Biol Chem 290:941-9
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
Hadigal, Satvik R; Agelidis, Alex M; Karasneh, Ghadah A et al. (2015) Heparanase is a host enzyme required for herpes simplex virus-1 release from cells. Nat Commun 6:6985

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