title: Antitumor efficacy of the heparanase inhibitor SST0001 alone and in combination with antiangiogenic agents in the treatment of human pediatric sarcoma models.
abstract: The activity of heparanase is responsible for heparan sulfate cleavage, thus resulting in the release of heparan sulfate-bound growth factors. Since heparanase activity is upregulated in several tumor types and is implicated in the malignant behavior, the enzyme is regarded as a promising target for antitumor therapy. Based on previous evidence that the heparanase inhibitor SST0001, a non-anticoagulant N-acetylated glycol split heparin, is effective against an Ewing's sarcoma model, the present study was performed to extend the preclinical evaluation of SST0001 to a panel of pediatric sarcoma models, representative of various tumor histotypes (soft tissue and bone sarcomas) and to further elucidate its mode of action. SST0001 treatment downregulated several angiogenic factors in the conditioned media of sarcoma cells, inhibited the pro-invasive effect of heparin-binding factors (VEGF, bFGF, HGF, PDGF), and abrogated PDGF receptor tyrosine phosphorylation. Subcutaneous administration of SST0001 was very effective, resulting in a significant growth inhibition (range, 64-95%) of all tested tumor xenografts. The efficacy of SST0001 was enhanced in combination with antiangiogenic agents (bevacizumab, sunitinib) as documented by the high rate of complete response. The synergistic effect of SST0001 in combination with antiangiogenic agents is consistent with the heparanase mode of action and with the relevant role of heparin-binding proangiogenic/growth factors in the malignant behavior of sarcoma cells.
authors: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
authors: G
authors: G
authors: Cassinelli
authors: C
authors: C
authors: Lanzi
authors: M
authors: M
authors: Tortoreto
authors: D
authors: D
authors: Cominetti
authors: G
authors: G
authors: Petrangolini
authors: E
authors: E
authors: Favini
authors: N
authors: N
authors: Zaffaroni
authors: C
authors: C
authors: Pisano
authors: S
authors: S
authors: Penco
authors: I
authors: I
authors: Vlodavsky
authors: F
authors: F
authors: Zunino
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D000068258:Bevacizumab; D001859:Bone Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects; D002648:Child; D004357:Drug Synergism; D005260:Female; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006493:Heparin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D012516:Osteosarcoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D012208:Rhabdomyosarcoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D000077210:Sunitinib; D023041:Xenograft Model Antitumor Assays; D000099175:Heparanase
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068258:Bevacizumab; D005966:Glucuronidase; D006493:Heparin; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib; D000099175:Heparanase; C559639:SST 0001