A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours

Dredge, Keith; Brennan, Todd V.; Hammond, Edward; Lickliter, Jason D.; Lin, Li-Wen; Bampton, Darryn; Handley, Paul; Lankesheer, Fleur; Morrish, Glynn; Yang, Yiping; Brown, Michael P.; Millward, Michael

doi:10.1038/s41416-018-0006-0

Cited by 78 publications

(83 citation statements)

References 38 publications

(45 reference statements)

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“…PG545 has been selected over the PG500 series of heparan sulfate mimetics for the ability to inhibit both angiogenesis and heparanase activity and was selected as the lead clinical candidate for oncology [191]. Eight years after, PG545 was then evaluated on a Phase I study in patients with advanced solid malignancies that had relapsed or was refractory to standard therapy, and showed a disease control up to 24 weeks in 38% of evaluable subjects with increases in innate immune cell activation, plasma IFNγ, TNFα, IP-10, and MCP-1 [192].…”

Section: Clinical Considerationsmentioning

confidence: 99%

The Challenge of Modulating Heparan Sulfate Turnover by Multitarget Heparin Derivatives

2020

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This review comes as a part of the special issue “Emerging frontiers in GAGs and mimetics”. Our interest is in the manipulation of heparan sulfate (HS) turnover by employing HS mimetics/heparin derivatives that exert pleiotropic effects and are interesting for interfering at multiple levels with pathways in which HS is implicated. Due to the important role of heparanase in HS post-biosynthetic modification and catabolism, we focus on the possibility to target heparanase, at both extracellular and intracellular levels, a strategy that can be applied to many conditions, from inflammation to cancer and neurodegeneration.

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Section: Clinical Considerationsmentioning

confidence: 99%

The Challenge of Modulating Heparan Sulfate Turnover by Multitarget Heparin Derivatives

2020

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“…Immunohistochemistry, in situ hybridization, quantitative polymerase chain reaction (qPCR) and immunoblot analyses demonstrate that heparanase expression is enhanced in all major types of cancers (i.e., carcinomas, sarcomas and hematological malignancies) . Numerous clinical association studies have consistently demonstrated that upregulated heparanase expression correlates with enhanced metastasis and poor prognosis, thus confirming the prometastatic function of heparanase and encouraging the development of heparanase inhibitors as antitumor therapeutics . More recent studies provided compelling evidence that tie heparanase with all steps of tumor formation including tumor initiation, growth, metastasis and chemoresistance .…”

Section: Introductionmentioning

confidence: 98%

Heparanase promotes glioma progression via enhancing CD24 expression

Barash

Spyrou

Liu

et al. 2019

Intl Journal of Cancer

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Heparanase is an endo-β-D-glucuronidase that cleaves heparan sulfate (HS) side chains of heparan sulfate proteoglycans. Compelling evidence tie heparanase levels with all steps of tumor formation including tumor initiation, growth, metastasis and chemo-resistance, likely involving augmentation of signaling pathways and gene transcription. In order to reveal the molecular mechanism(s) underlying the protumorigenic properties of heparanase, we established an inducible (Tet-on) system in U87 human glioma cells and applied gene array methodology in order to identify genes associated with heparanase induction. We found that CD24, a mucin-like cell adhesion protein, is consistently upregulated by heparanase and by heparanase splice variant devoid of enzymatic activity, whereas heparanase gene silencing was associated with decreased CD24 expression. This finding was further substantiated by a similar pattern of heparanase and CD24 immunostaining in glioma patients (Pearson's correlation; R = 0.66, p = 0.00001). Noteworthy, overexpression of CD24 stimulated glioma cell migration, invasion, colony formation in soft agar and tumor growth in mice suggesting that CD24 functions promote tumor growth. Likewise, anti-CD24 neutralizing monoclonal antibody attenuated glioma tumor growth, and a similar inhibition was observed in mice treated with a neutralizing mAb directed against L1 cell adhesion molecule (L1CAM), a ligand for CD24. Importantly, significant shorter patient survival was found in heparanase-high/CD24-high tumors vs. heparanase-high/CD24-low tumors for both high-grade and low-grade glioma (p = 0.02). Our results thus uncover a novel heparanase-CD24-L1CAM axis that plays a significant role in glioma tumorigenesis.

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“…Heparan sulfate mimetics have emerged as potential therapies against various types of cancer (1)(2)(3)(4). These agents are thought to work via inhibition of heparanase (5)(6)(7), an enzyme associated with tumor cell invasion and angiogenesis (6,8,9).…”

Section: Introductionmentioning

confidence: 99%

“…PG545 is reported to function by blocking the catalytic center of heparinase and competing for the HSbinding domain (11,19). PG545 is currently under evaluation in human clinical trials for use in treating solid tumors after having demonstrated efficacy against tumor angiogenesis and metastasis in multiple animal studies (1,3,20,21). PG545 has also demonstrated efficacy against lymphoma and may also have utility in other, non-neoplastic inflammatory disorders, such as acute kidney injury, atherosclerosis, and viral infection (2,9,22,23).…”

Section: Introductionmentioning

confidence: 99%

The Heparan Sulfate Mimetic PG545 Modulates T Cell Responses and Prevents Delayed-Type Hypersensitivity

et al. 2020

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The heparan sulfate mimetic PG545 (pixatimod) is under evaluation as an inhibitor of angiogenesis and metastasis including in human clinical trials. We have examined the effects of PG545 on lymphocyte phenotypes and function. We report that PG545 treatment suppresses effector T cell activation and polarizes T cells away from Th17 and Th1 and toward Foxp3+ regulatory T cell subsets in vitro and in vivo. Mechanistically, PG545 inhibits Erk1/2 signaling, a pathway known to affect both T cell activation and subset polarization. Interestingly, these effects are also observed in heparanase-deficient T cells, indicating that PG545 has effects that are independent of its role in heparanase inhibition. Consistent with these findings, administration of PG545 in a Th1/Th17-dependent mouse model of a delayed-type hypersensitivity led to reduced footpad inflammation, reduced Th17 memory cells, and an increase in FoxP3+ Treg proliferation. PG545 also promoted Foxp3+ Treg induction by human T cells. Finally, we examined the effects of other heparan sulfate mimetics PI-88 and PG562 on lymphocyte polarization and found that these likewise induced Foxp3+ Treg in vitro but did not reduce Th17 numbers or improve delayed-type hypersensitivity in this model. Together, these data indicate that PG545 is a potent inhibitor of Th1/Th17 effector functions and inducer of FoxP3+ Treg. These findings may inform the adaptation of PG545 for clinical applications including in inflammatory pathologies associated with type IV hypersensitivity responses.

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A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours

Cited by 78 publications

References 38 publications

The Challenge of Modulating Heparan Sulfate Turnover by Multitarget Heparin Derivatives

The Challenge of Modulating Heparan Sulfate Turnover by Multitarget Heparin Derivatives

Heparanase promotes glioma progression via enhancing CD24 expression

The Heparan Sulfate Mimetic PG545 Modulates T Cell Responses and Prevents Delayed-Type Hypersensitivity

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