Abstract
The heparan sulfate (HS) mimic/heparanase inhibitor roneparstat (SST0001) shows antitumor activity in preclinical sarcoma models. We hypothesized that this 100% N-acetylated and glycol-split heparin could interfere with the functions of several receptor tyrosine kinases (RTK) coexpressed in sarcomas and activated by heparin-binding growth factors. Using a phospho-proteomic approach, we investigated the drug effects on RTK activation in human cell lines representative of different sarcoma subtypes. Inhibition of FGF, IGF, ERBB and PDGF receptors by the drug was biochemically and functionally validated. Roneparstat counteracted the autocrine loop induced by the COL1A1/PDGFB fusion oncogene, expressed in a human dermatofibrosarcoma protuberans primary culture and in NIH3T3COL1A1/PDGFB transfectants, inhibiting cell anchorage-independent growth and invasion. In addition, roneparstat inhibited the activation of cell surface PDGFR and PDGFR-associated FAK, likely contributing to the reversion of NIH3T3COL1A1/PDGFB cell transformed and pro-invasive phenotype. Biochemical and histological/immunohistochemical ex vivo analyses confirmed a reduced activation of ERBB4, EGFR, INSR, IGF1R, associated with apoptosis induction and angiogenesis inhibition in a drug-treated Ewing's sarcoma family tumor xenograft. The combination of roneparstat with irinotecan significantly improved the antitumor effect against A204 rhabdoid xenografts resulting in a high rate of complete responses and cures. These findings reveal that roneparstat exerts a multi-target inhibition of RTKs relevant in the pathobiology of different sarcoma subtypes. These effects, likely cooperating with heparanase inhibition, contribute to the antitumor efficacy of the drug. The study supports heparanase/HS axis targeting as a valuable approach in combination therapies of different sarcoma subtypes providing a preclinical rationale for clinical investigation.
Highlights
Sarcomas are a highly heterogeneous group of rare aggressive tumors arising either in bones or soft tissues
We applied an explorative approach based on the phospho-proteomic profiling of receptor tyrosine kinases (RTK) to simultaneously detect the activation of multiple receptors in lysates from control and roneparstat-treated sarcoma cell lines including Ewing’s sarcoma (ES) family tumors (ESFT), RMS, OS and synovial sarcoma (SS)
Whereas the inhibition of tyrosine phosphorylation of PDGFR and ERBB family members was a common event in roneparstattreated cells from the different sarcoma histotypes, the drug interference on the activation of other receptors (i.e. IGF1R, FGFR4) was found to occur in a cell line-specific way (Figure 1)
Summary
Sarcomas are a highly heterogeneous group of rare aggressive tumors arising either in bones or soft tissues. A TK inhibitor targeting ABL, KIT and PDGFR, has shown impressive efficacy in gastrointestinal stromal tumors carrying gain-of-function KIT or PDGFRA mutations, and in dermatofibrosarcoma protuberans (DFSP) characterized by overactivation of PDGFR due to a collagen 1A1 (COL1A1)/ PDGFB rearrangement [4, 5]. Such therapeutic success, relying on a condition of ‘oncogene addiction’ [6], has not been reproduced in other sarcoma types. Most of these tumors might not be dependent on a single targetable signaling pathway due to the high biomolecular complexity
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