Research Papers:

Targeting heparanase overcomes chemoresistance and diminishes relapse in myeloma

Vishnu C. Ramani, Fenghuang Zhan, Jianbo He, Paola Barbieri, Alessandro Noseda, Guido Tricot and Ralph D. Sanderson _

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Oncotarget. 2016; 7:1598-1607. https://doi.org/10.18632/oncotarget.6408

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Vishnu C. Ramani1,2, Fenghuang Zhan3,4, Jianbo He1, Paola Barbieri5, Alessandro Noseda5, Guido Tricot3,4, Ralph D. Sanderson1,2

1Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

2Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA

3Department of Internal Medicine, University of Iowa, Iowa City, IA, USA

4Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA

5Sigma-tau Research Switzerland S.A., Mendrisio, Switzerland

Correspondence to:

Ralph D. Sanderson, e-mail: [email protected]

Keywords: heparanase, multiple myeloma, roneparstat, drug resistance, chemotherapy

Received: July 28, 2015     Accepted: November 16, 2015     Published: November 27, 2015


In most myeloma patients, even after several rounds of intensive therapy, drug resistant tumor cells survive and proliferate aggressively leading to relapse. In the present study, gene expression profiling of tumor cells isolated from myeloma patients after sequential rounds of chemotherapy, revealed for the first time that heparanase, a potent promoter of myeloma growth and progression, was elevated in myeloma cells that survived therapy. Based on this clinical data, we hypothesized that heparanase was involved in myeloma resistance to drug therapy. In several survival and viability assays, elevated heparanase expression promoted resistance of myeloma tumor cells to chemotherapy. Mechanistically, this enhanced survival was due to heparanase-mediated ERK signaling. Importantly, use of the heparanase inhibitor Roneparstat in combination with chemotherapy clearly diminished the growth of disseminated myeloma tumors in vivo. Moreover, use of Roneparstat either during or after chemotherapy diminished regrowth of myeloma tumors in vivo following therapy. These results provide compelling evidence that heparanase is a promising, novel target for overcoming myeloma resistance to therapy and that targeting heparanase has the potential to prevent relapse in myeloma and possibly other cancers.

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