Supersulfated low-molecular weight heparin synergizes with IGF1R/IR inhibitor to suppress synovial sarcoma growth and metastases

Non-Anticoagulant Heparins as Heparanase Inhibitors

“…Tested in vivo in the metastatic B16 melanoma model, it exhibited antimetastatic activity similar to that of UFH [61]. Recently, a remarkable antitumor activity of ssLMWH has been demonstrated both in vitro and in vivo in synovial sarcoma experimental models [83]. Inhibition of synovial sarcoma cell growth and invasion was associated with downregulation of the activity of receptor tyrosine kinases of the EGFR, PDGFR and IGFIR families and heparanase inhibition.…”

“…The combination of ssLMWH with an inhibitor of IGF receptors, synergistically inhibited cell proliferation and motility and promoted apoptosis. In vivo ssLMWH synergized with the receptor tyrosine kinase inhibitor to suppress orthotopic synovial sarcoma growth and spontaneous lung metastatic dissemination [83]. However, it is necessary to consider the risk that derivatives with a high degree of sulfation, may stimulate other competitive biological mechanism or cause unwanted reactions such as the activation of prekallikrein as observed with oversulfated chondroitin sulfate, known as OSCS [84,85].…”

The Challenge of Modulating Heparan Sulfate Turnover by Multitarget Heparin Derivatives

“…Some supersulfated low-molecular weight heparins (ssLMWH) have been synthesized with low anticoagulant activity despite the high degree of sulfation and were shown to reduce synovial sarcoma growth and metastases in vitro and in vivo by interfering with the activity of heparanase, growth factor/receptor axes and proinflammatory molecules (e.g., leucocyte elastase and cathepsin G) [168]. Another compound, SSLMW-19, a key factor in the regulation of iron metabolism, and also involved in carcinogenesis and metastasis, was shown to rapidly and strongly inhibit the expression of hepcidin in vitro and in vivo [169].…”

Targeting the undruggable: exploiting neomorphic features of fusion oncoproteins in childhood sarcomas for innovative therapies

“…Yet, given the outstanding preclinical results obtained when blocking this pathway, significant efforts are being made to develop combined therapies that could overcome these hurdles. For instance, a recent report suggests combining heparanase inhibitors with IGF-1R antagonists for treatment of metastatic SS [170], and a combined therapy including BET inhibitors has been set forth for EwS [171]. In the case of ARMS, it has been proposed that the simultaneous inhibition of IGF-1R and additional tyrosine kinases could help to overcome resistance to treatment.…”