PG545, a dual heparanase and angiogenesis inhibitor, induces potent anti-tumour and anti-metastatic efficacy in preclinical models

Dredge, Keith; Hammond, Edward; Handley, Paul; Gonda, Thomas J.; Smith, Maree T.; Vincent, Christina; Brandt, Ralf; Ferro, Vito; Bytheway, Ian

doi:10.1038/bjc.2011.11

Cited by 156 publications

(185 citation statements)

References 32 publications

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“…heparanase inhibitor, PG545 (19). We found that the growth of tumor xenografts produced by Burkitt's (Ramos, Raji, Daudi), diffuse (OCI-LY-19), and follicular (SU-DHL-6) lymphoma cells was markedly attenuated by PG545 (Fig.…”

Section: Significancementioning

confidence: 88%

See 1 more Smart Citation

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Weissmann¹,

Arvatz²,

Horowitz

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

106

140

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Heparanase is an endoglycosidase that cleaves heparan sulfate side chains of proteoglycans, resulting in disassembly of the extracellular matrix underlying endothelial and epithelial cells and associating with enhanced cell invasion and metastasis. Heparanase expression is induced in carcinomas and sarcomas, often associating with enhanced tumor metastasis and poor prognosis. In contrast, the function of heparanase in hematological malignancies (except myeloma) was not investigated in depth. Here, we provide evidence that heparanase is expressed by human follicular and diffused non-Hodgkin's B-lymphomas, and that heparanase inhibitors restrain the growth of tumor xenografts produced by lymphoma cell lines. Furthermore, we describe, for the first time to our knowledge, the development and characterization of heparanaseneutralizing monoclonal antibodies that inhibit cell invasion and tumor metastasis, the hallmark of heparanase activity. Using luciferase-labeled Raji lymphoma cells, we show that the heparanase-neutralizing monoclonal antibodies profoundly inhibit tumor load in the mouse bones, associating with reduced cell proliferation and angiogenesis. Notably, we found that Raji cells lack intrinsic heparanase activity, but tumor xenografts produced by this cell line exhibit typical heparanase activity, likely contributed by host cells composing the tumor microenvironment. Thus, the neutralizing monoclonal antibodies attenuate lymphoma growth by targeting heparanase in the tumor microenvironment.heparanase | lymphoma | neutralizing antibody | tumor growth | metastasis H eparanase is an endo-β-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains at a limited number of sites, releasing saccharide products with appreciable size (4-7 kDa) and biological potency. Enzymatic degradation of HS leads to disassembly of the extracellular matrix (ECM) and correlates with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of HS cleavage and remodeling of the ECM and basement membrane underlying epithelial and endothelial cells (1, 2). Heparanase expression is induced in human cancer, most often associating with reduced patients' survival postoperation, increased tumor metastasis, and higher vessel density (3-5). In addition, heparanase up-regulation is associated with tumors larger in size (3, 5). Likewise, heparanase over-expression enhanced (6, 7), whereas local delivery of anti-heparanase siRNA inhibited (8), the growth of tumor xenografts. These results imply that heparanase function is not limited to tumor metastasis but is engaged in progression of the primary lesion, thus critically supporting the intimate involvement of heparanase in tumor progression and encouraging the development of heparanase inhibitors as anticancer therapeutics (9-12). As a consequence, heparanase inhibitors are currently evaluated in phase 1 clinical trials (13).Heparanase activity is similarly implicated in the progression of multiple myeloma (14-16), but its significan...

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Section: Significancementioning

confidence: 88%

“…Although PG545 appears as a potent inhibitor that attenuates the progression of several carcinomas (19) and lymphomas ( Fig. 1), it also exhibits heparanase-unrelated properties and impedes the signaling of HS-bound growth-and angiogenesispromoting factors (21).…”

Section: Inhibition Of Lymphoma Xenograft Growth By Heparanase-neutramentioning

confidence: 99%

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Weissmann¹,

Arvatz²,

Horowitz

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

106

140

View full text Add to dashboard Cite

show abstract

“…Indeed, HS mimetics have demonstrated antitumor activities in multiple preclinical studies of metastatic solid tumors in mice (14)(15)(16)(17). Moreover, a number of HS mimetics are currently under clinical investigation for various cancers -muparfostat in hepatitis virus-related hepatocellular carcinoma after surgical resection, roneparstat in multiple myeloma, and necuparanib in pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

Heparan sulfate mimetic PG545-mediated antilymphoma effects require TLR9-dependent NK cell activation

Brennan¹,

Lin²,

Brandstadter³

et al. 2015

Journal of Clinical Investigation

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“…Heparan sulfate mimetics are highly sulfated oligosaccharides that inhibit heparanase, sequester HSPG-binding factors, and inhibit SULF2 [66][67][68]. In preclinical studies, HS mimetics have effectively targeted multiple HSPG-dependent phenotypes and have resulted in decreased in vivo tumor growth, tumor invasion, tumor metastasis, and angiogenesis [61,69].…”

Section: Hspgs and The Enzymes That Regulate Them As Potential Therapmentioning

confidence: 99%

Novel Therapeutic Targets in the Brain Tumor Microenvironment

Phillips

2012

Oncotarget

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ABSTRACT:Glioblastoma (GBM), a highly malignant brain tumor of adults and children, diffusely invades within the non-neoplastic brain. Despite aggressive current therapeutic interventions, improved therapeutic strategies are greatly needed. Interactions between the tumor and constituents of its microenvironment are known to regulate malignancy, and heparan sulfate proteoglycans (HSPGs) are important as they bind diverse extracellular proteins, including growth factors and cell adhesion molecules, regulating the activity of several ligand-mediated signaling pathways. Recent work from our group described a mechanism by which GBM regulates PDGFR-alpha signaling via enzymatic alteration of heparan sulfate proteoglycans (HSPGs) in the extracellular microenvironment. Blocking tumor-induced alterations of HSPGs, which can be achieved by pharmacological strategies, would potentially inhibit multiple oncogenic signaling pathways in tumor cells and disrupt critical tumormicroenvironment interactions. Here we examine HSPGs and the enzymes that modify them in GBM. We compare their expression across tumor subtypes, their potential roles in oncogenesis, and their potential as novel therapeutic targets in GBM.

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PG545, a dual heparanase and angiogenesis inhibitor, induces potent anti-tumour and anti-metastatic efficacy in preclinical models

Cited by 156 publications

References 32 publications

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Heparan sulfate mimetic PG545-mediated antilymphoma effects require TLR9-dependent NK cell activation

Novel Therapeutic Targets in the Brain Tumor Microenvironment

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