Roneparstat: Development, Preclinical and Clinical Studies

Noseda, Alessandro; Barbieri, Paola

doi:10.1007/978-3-030-34521-1_21

Cited by 26 publications

(36 citation statements)

References 42 publications

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“…In most tumor types, heparanase was reported to be overexpressed and correlated with increased tumor size, angiogenesis, metastasis and poor prognosis ( 8 , 32 – 37 ). In line with the notion that heparanase is a drug target, three inhibitors of the heparanase enzyme (Roneparstat, Necuparanib, Pixatimod) have been evaluated in early-stage clinical trials, showing signs of efficacy ( 38 – 41 ). In addition, heparanase is capable of regulating multiple aspects of the inflammatory process ( 8 , 11 ).…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori-Induced Heparanase Promotes H. pylori Colonization and Gastritis

Tang

Lei

et al. 2021

Front. Immunol.

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Chronic gastritis caused by Helicobacter pylori (H. pylori) infection has been widely recognized as the most important risk factor for gastric cancer. Analysis of the interaction between the key participants in gastric mucosal immunity and H. pylori infection is expected to provide important insights for the treatment of chronic gastritis and the prevention of gastric cancer. Heparanase is an endoglycosidase that degrades heparan sulfate, resulting in remodeling of the extracellular matrix thereby facilitating the extravasation and migration of immune cells towards sites of inflammation. Heparanase also releases heparan sulfate-bound cytokines and chemokines that further promote directed motility and recruitment of immune cells. Heparanase is highly expressed in a variety of inflammatory conditions and diseases, but its role in chronic gastritis has not been sufficiently explored. In this study, we report that H. pylori infection promotes up-regulation of heparanase in gastritis, which in turn facilitates the colonization of H. pylori in the gastric mucosa, thereby aggravating gastritis. By sustaining continuous activation, polarization and recruitment of macrophages that supply pro-inflammatory and pro-tumorigenic cytokines (i.e., IL-1, IL-6, IL-1β, TNF-α, MIP-2, iNOS), heparanase participates in the generation of a vicious circle, driven by enhanced NFκB and p38-MAPK signaling, that supports the development and progression of gastric cancer. These results suggest that inhibition of heparanase may block this self-sustaining cycle, and thereby reduce the risk of gastritis and gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Helicobacter pylori-Induced Heparanase Promotes H. pylori Colonization and Gastritis

Tang

Lei

et al. 2021

Front. Immunol.

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“…101 Given the importance of exosomes in intercellular communication in disease states such as cancer and inflammation, syndecans and heparanase represent viable targets for blocking exosome biogenesis and function. Roneparstat, a heparanase inhibitor composed of modified heparin, 104 can block exosome docking with recipient cells and antiheparanase monoclonal antibody can inhibit exosome-mediated migration of macrophages. 101,102 Future studies on the role of syndecans and heparanase in the regulation of exosome biogenesis, composition, and function will likely uncover additional ways in which to target exosomes therapeutically.…”

Section: Exosomesmentioning

confidence: 99%

Biology of the Heparanase–Heparan Sulfate Axis and Its Role in Disease Pathogenesis

Vlodavsky

Barash

Nguyen

et al. 2021

Semin Thromb Hemost

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Cell surface proteoglycans are important constituents of the glycocalyx and participate in cell–cell and cell–extracellular matrix (ECM) interactions, enzyme activation and inhibition, and multiple signaling routes, thereby regulating cell proliferation, survival, adhesion, migration, and differentiation. Heparanase, the sole mammalian heparan sulfate degrading endoglycosidase, acts as an “activator” of HS proteoglycans, thus regulating tissue hemostasis. Heparanase is a multifaceted enzyme that together with heparan sulfate, primarily syndecan-1, drives signal transduction, immune cell activation, exosome formation, autophagy, and gene transcription via enzymatic and nonenzymatic activities. An important feature is the ability of heparanase to stimulate syndecan-1 shedding, thereby impacting cell behavior both locally and distally from its cell of origin. Heparanase releases a myriad of HS-bound growth factors, cytokines, and chemokines that are sequestered by heparan sulfate in the glycocalyx and ECM. Collectively, the heparan sulfate–heparanase axis plays pivotal roles in creating a permissive environment for cell proliferation, differentiation, and function, often resulting in the pathogenesis of diseases such as cancer, inflammation, endotheliitis, kidney dysfunction, tissue fibrosis, and viral infection.

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“…For in vitro studies, these drugs were dissolved in DMSO and further diluted in cell culture medium (0.1-0.5% DMSO final concentration). The HS mimetic/ heparanase inhibitor SST0001 (roneparstat, 100 NA-ROH) [52], was provided by Leadiant Biosciences S.p.a., (Rome, IT); SST0762NA1, a biotinylated structural analog of SST0001, provided by G. Ronzoni Institute for Chemical and Biochemical Research (Milan, IT), was prepared by conjugation on NH 2 group of glucosamine residues with biotin N-hydroxysuccinimide ester, as previously reported for compound B1 [40]. SST0762NA1 has Mw of 7800 Da and about 2 biotin moieties for heparin chain.…”

Section: Drugsmentioning

confidence: 99%

Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma

Lanzi

Favini

et al. 2021

J Exp Clin Cancer Res

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Background Synovial sarcoma (SS) is an aggressive soft tissue tumor with limited therapeutic options in advanced stage. SS18-SSX fusion oncogenes, which are the hallmarks of SS, cause epigenetic rewiring involving histone deacetylases (HDACs). Promising preclinical studies supporting HDAC targeting for SS treatment were not reflected in clinical trials with HDAC inhibitor (HDACi) monotherapies. We investigated pathways implicated in SS cell response to HDACi to identify vulnerabilities exploitable in combination treatments and improve the therapeutic efficacy of HDACi-based regimens. Methods Antiproliferative and proapoptotic effects of the HDACi SAHA and FK228 were examined in SS cell lines in parallel with biochemical and molecular analyses to bring out cytoprotective pathways. Treatments combining HDACi with drugs targeting HDACi-activated prosurvival pathways were tested in functional assays in vitro and in a SS orthotopic xenograft model. Molecular mechanisms underlying synergisms were investigated in SS cells through pharmacological and gene silencing approaches and validated by qRT-PCR and Western blotting. Results SS cell response to HDACi was consistently characterized by activation of a cytoprotective and auto-sustaining axis involving ERKs, EGR1, and the β-endoglycosidase heparanase, a well recognized pleiotropic player in tumorigenesis and disease progression. HDAC inhibition was shown to upregulate heparanase by inducing expression of the positive regulator EGR1 and by hampering negative regulation by p53 through its acetylation. Interception of HDACi-induced ERK-EGR1-heparanase pathway by cell co-treatment with a MEK inhibitor (trametinib) or a heparanase inhibitor (SST0001/roneparstat) enhanced antiproliferative and pro-apoptotic effects. HDAC and heparanase inhibitors had opposite effects on histone acetylation and nuclear heparanase levels. The combination of SAHA with SST0001 prevented the upregulation of ERK-EGR1-heparanase induced by the HDACi and promoted caspase-dependent cell death. In vivo, the combined treatment with SAHA and SST0001 potentiated the antitumor efficacy against the CME-1 orthotopic SS model as compared to single agent administration. Conclusions The present study provides preclinical rationale and mechanistic insights into drug combinatory strategies based on the use of ERK pathway and heparanase inhibitors to improve the efficacy of HDACi-based antitumor therapies in SS. The involvement of classes of agents already clinically available, or under clinical evaluation, indicates the transferability potential of the proposed approaches.

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Roneparstat: Development, Preclinical and Clinical Studies

Cited by 26 publications

References 42 publications

Helicobacter pylori-Induced Heparanase Promotes H. pylori Colonization and Gastritis

Helicobacter pylori-Induced Heparanase Promotes H. pylori Colonization and Gastritis

Biology of the Heparanase–Heparan Sulfate Axis and Its Role in Disease Pathogenesis

Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma

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