Abstract |
Synovial sarcoma (SS) is an aggressive tumor with propensity for lung metastases which significantly impact patients' prognosis. New therapeutic approaches are needed to improve treatment outcome. Targeting the heparanase/ heparan sulfate proteoglycan system by heparin derivatives which act as heparanase inhibitors/ heparan sulfate mimetics is emerging as a therapeutic approach that can sensitize the tumor response to chemotherapy. We investigated the therapeutic potential of a supersulfated low molecular weight heparin (ssLMWH) in preclinical models of SS. ssLMWH showed a potent anti- heparanase activity, dose-dependently inhibited SS colony growth and cell invasion, and downregulated the activation of receptor tyrosine kinases including IGF1R and IR. The combination of ssLMWH and the IGF1R/IR inhibitor BMS754807 synergistically inhibited proliferation of cells exhibiting IGF1R hyperactivation, also abrogating cell motility and promoting apoptosis in association with PI3K/AKT pathway inhibition. The drug combination strongly enhanced the antitumor effect against the CME-1 model, as compared to single agent treatment, abrogating orthotopic tumor growth and significantly repressing spontaneous lung metastatic dissemination in treated mice. These findings provide a strong preclinical rationale for developing drug regimens combining heparanase inhibitors/HS mimetics with IGF1R antagonists for treatment of metastatic SS.
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Authors | Giuliana Cassinelli, Laura Dal Bo, Enrica Favini, Denis Cominetti, Sabina Pozzi, Monica Tortoreto, Michelandrea De Cesare, Daniele Lecis, Eugenio Scanziani, Lucia Minoli, Annamaria Naggi, Israel Vlodavsky, Nadia Zaffaroni, Cinzia Lanzi |
Journal | Cancer letters
(Cancer Lett)
Vol. 415
Pg. 187-197
(02 28 2018)
ISSN: 1872-7980 [Electronic] Ireland |
PMID | 29225052
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2017 Elsevier B.V. All rights reserved. |
Chemical References |
- BMS 754807
- Heparin, Low-Molecular-Weight
- IGF1R protein, human
- Pyrazoles
- Receptors, Somatomedin
- Sulfates
- Triazines
- Receptor, IGF Type 1
- heparanase
- Glucuronidase
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Topics |
- Animals
- Antineoplastic Combined Chemotherapy Protocols
(pharmacology)
- Apoptosis
(drug effects)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Drug Synergism
- Glucuronidase
(antagonists & inhibitors, metabolism)
- Heparin, Low-Molecular-Weight
(administration & dosage, metabolism, pharmacology)
- Humans
- Mice, SCID
- Neoplasm Metastasis
- Pyrazoles
(administration & dosage, pharmacology)
- Receptor, IGF Type 1
- Receptors, Somatomedin
(antagonists & inhibitors, metabolism)
- Sarcoma, Synovial
(drug therapy, metabolism, pathology)
- Sulfates
- Triazines
(administration & dosage, pharmacology)
- Xenograft Model Antitumor Assays
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