title: Targeting heparanase overcomes chemoresistance and diminishes relapse in myeloma.
abstract: 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.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.|Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Vishnu C
authors.initials: VC
authors.lastname: Ramani
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.|Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.
authors.forename: Fenghuang
authors.initials: F
authors.lastname: Zhan
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Jianbo
authors.initials: J
authors.lastname: He
authors.affiliation: Sigma-tau Research Switzerland S.A., Mendrisio, Switzerland.
authors.forename: Paola
authors.initials: P
authors.lastname: Barbieri
authors.affiliation: Sigma-tau Research Switzerland S.A., Mendrisio, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Noseda
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.|Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Tricot
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.|Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Ralph D
authors.initials: RD
authors.lastname: Sanderson
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005966:Glucuronidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D065089:Glycoside Hydrolase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D012008:Recurrence; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D065089:Glycoside Hydrolase Inhibitors; D000099175:Heparanase
keywords: chemotherapy; drug resistance; heparanase; multiple myeloma; roneparstat