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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., Competing Interests: Roneparstat is a proprietary drug of sigma-tau Research Switzerland S.A. F. Zunino and N. Zaffaroni received grant support from sigma-tau Research Switzerland S.A. The other authors disclosed no potential conflict of interest.

Background: The objective of this study was to report on a retrospective series of patients with epithelioid hemangioendothelioma (EHE) who received treatment with sirolimus within the Italian Rare Cancer Network. Methods: From January 2005, 38 adult patients with advanced EHE received continuous‐dosing sirolimus, 5 mg daily, until they developed either toxicity or disease progression. Disease progression in the 6 months before the start of treatment was required. Each pathologic diagnosis was reviewed. The daily dose of sirolimus was adjusted based on plasma levels. Response was retrospectively assessed by local investigators using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST). Survival was estimated using the Kaplan‐Meier method. Results: All 38 patients (WW Domain Containing Transcription Regulator 1 [WWTR1]‐positive, n = 37; transcription factor E3 [TFE3]‐positive, n = 1) had disease progression before starting sirolimus (at baseline, 13 of 38 patients had the presence of serosal effusions and systemic symptoms). Thirty‐seven patients were evaluable for response (there was 1 early interruption). The best RECIST responses were a partial response in 4 patients (10.8%), stable disease in 28 patients (75.7%), and disease progression in 5 patients (13.5%). At a 41.5‐month median follow‐up (interquartile range [IQR], 23.9‐56.8 months), the median PFS was 13 months (95% CI, 3.7 months to not estimated [NE]), and the median OS was 18.8 months (95% CI, 10.6 months to NE). In patients who had serosal effusions at baseline, the median PFS was 4.8 months (IQR, 3.5‐11.7 months), and the median OS was 10.6 months (IQR, 5.1‐13.0 months), compared with 47.8 months (IQR, 11.4 months to NE) and 47.8 months (IQR, 15.7 months to NE), respectively, in patients without serosal effusions. Overall, sirolimus was fairly well tolerated, with 10 patients reporting irregular menstruation/ovary disfunction. Conclusions: The current results confirm that sirolimus is active in EHE, leading to prolonged stabilization in most patients who present without serosal effusions. Serosal effusions are confirmed as an unfavorable prognostic sign associated with short survival, and sirolimus displays limited activity in this subgroup. In a large retrospective study of systemic treatment for epithelioid hemangioendothelioma, sirolimus achieved prolonged disease stabilization in patients who previously had progressive, advanced disease, with a 10% overall risk ratio according to RECIST, an overall median progression‐free survival of 13 months, and a median progression‐free survival of 47.8 months in patients without serosal effusion. In patients who had serosal effusion, however, sirolimus had limited activity, and patients had a poor prognosis, with a median survival less than 1 year. [ABSTRACT FROM AUTHOR]

Keywords: sarcoma; molecular diagnosis; fusion transcripts; NGS; anchored multiplex PCR; hybrid capture-based panel EN sarcoma molecular diagnosis fusion transcripts NGS anchored multiplex PCR hybrid capture-based panel 1 2 2 06/26/20 20200623 NES 200623 In the original article, the Ethics Statement was incomplete as it only included the name of one of the institutions. Sarcoma, molecular diagnosis, fusion transcripts, NGS, anchored multiplex PCR, hybrid capture-based panel. [Extracted from the article]