Targeting heparanase overcomes chemoresistance and diminishes relapse in myeloma
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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
Ralph D. Sanderson, e-mail: firstname.lastname@example.org
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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