Paul Handley

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

Background:PG545 is a heparan sulfate (HS) mimetic that inhibits tumour angiogenesis by sequestering angiogenic growth factors in the extracellular matrix (ECM), thus limiting subsequent binding to receptors. Importantly, PG545 also inhibits heparanase, the only endoglycosidase which cleaves HS chains in the ECM. The aim of the study was to assess PG545 in various solid tumour and metastasis models.Methods:The anti-angiogenic, anti-tumour and anti-metastatic properties of PG545 were assessed using in vivo angiogenesis, solid tumour and metastasis models. Pharmacokinetic (PK) data were also generated in tumour-bearing mice to gain an understanding of optimal dosing schedules and regimens.Results:PG545 was shown to inhibit angiogenesis in vivo and induce anti-tumour or anti-metastatic effects in murine models of breast, prostate, liver, lung, colon, head and neck cancers and melanoma. Enhanced anti-tumour activity was also noted when used in combination with sorafenib in a liver cancer model. PK data revealed that the half-life of PG545 was relatively long, with pharmacologically relevant concentrations of radiolabeled PG545 observed in liver tumours.Conclusion:PG545 is a new anti-angiogenic clinical candidate for cancer therapy. The anti-metastatic property of PG545, likely due to the inhibition of heparanase, may prove to be a critical attribute as the compound enters phase I clinical trials.

Discovery of PG545: A Highly Potent and Simultaneous Inhibitor of Angiogenesis, Tumor Growth, and Metastasis

Increasing the aglycone lipophilicity of a series of polysulfated oligosaccharide glycoside heparan sulfate (HS) mimetics via attachment of a steroid or long chain alkyl group resulted in compounds with significantly improved in vitro and ex vivo antiangiogenic activity. The compounds potently inhibited heparanase and HS-binding angiogenic growth factors and displayed improved antitumor and antimetastatic activity in vivo compared with the earlier series. Preliminary pharmacokinetic analyses also revealed significant increases in half-life following iv dosing, ultimately supporting less frequent dosing regimens in preclinical tumor models compared with other HS mimetics. The compounds also displayed only mild anticoagulant activity, a common side effect usually associated with HS mimetics. These efforts led to the identification of 3β-cholestanyl 2,3,4,6-tetra-O-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β-d-glucopyranoside, tridecasodium salt (PG545, 18) as a clinical candidate. Compound 18 was recently evaluated in a phase I clinical trial in cancer patients.

The PG500 series: novel heparan sulfate mimetics as potent angiogenesis and heparanase inhibitors for cancer therapy

SummaryHeparan sulfate mimetics, which we have called the PG500 series, have been developed to target the inhibition of both angiogenesis and heparanase activity. This series extends the technology underpinning PI-88, a mixture of highly sulfated oligosaccharides which reached Phase III clinical development for hepatocellular carcinoma. Advances in the chemistry of the PG500 series provide numerous advantages over PI-88. These new compounds are fully sulfated, single entity oligosaccharides attached to a lipophilic moiety, which have been optimized for drug development. The rational design of these compounds has led to vast improvements in potency compared to PI-88, based on in vitro angiogenesis assays and in vivo tumor models. Based on these and other data, PG545 has been selected as the lead clinical candidate for oncology and is currently undergoing formal preclinical development as a novel treatment for advanced cancer.

Mechanisms of heparanase inhibition by the heparan sulfate mimetic PG545 and three structural analogues

The tetrasaccharide heparan sulfate (HS) mimetic PG545, a clinical anti‐cancer candidate, is an inhibitor of the HS‐degrading enzyme heparanase. The kinetics of heparanase inhibition by PG545 and three structural analogues were investigated to understand their modes of inhibition. The cholestanol aglycon of PG545 significantly increased affinity for heparanase and also modified the inhibition mode. For the tetrasaccharides, competitive inhibition was modified to parabolic competition by the addition of the cholestanol aglycon. For the trisaccharides, partial competitive inhibition was modified to parabolic competition. A schematic model to explain these findings is presented.

Antifungal diene in leaves of various avocado cultivars

Leaves (both young and mature) of seventeen commercial avocado (Persea americana) cultivars have been analysed monthly throughout the year to measure the concentration and seasonal variation of the antifungal diene (Z,Z)-2-hydroxy-4-oxohenicosa-12,15-dien-1-yl acetate (persin)

9,10-Dihydroxy-1,8-cineole (1,3,3-Trimethyl-2-oxabicyclo[2.2.2]octane-10,11-diol)

The title compound (3) has been synthesized and its presence sought in the urinary metabolites of the brushtail possum.

2-Hydroxy-4-oxohenicosan-1-yl Acetate. Its Presence in Avocado and its Simple Chemistry

The title compound (1b) is present in avocado leaves. Simple chemistry of the compound is described.

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

BackgroundPG545 (pixatimod) is a novel immunomodulatory agent, which has been demonstrated to stimulate innate immune responses against tumours in preclinical cancer models.MethodsThis Phase I study investigated the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of PG545 monotherapy. Escalating doses of PG545 were administered to patients with advanced solid malignancies as a weekly 1-h intravenous infusion.ResultsTwenty-three subjects were enrolled across four cohorts (25, 50, 100 and 150 mg). Three dose-limiting toxicities (DLTs)—hypertension (2), epistaxis (1)—occurred in the 150 mg cohort. No DLTs were noted in the 100 mg cohort, which was identified as the maximum-tolerated dose. No objective responses were reported. Best response was stable disease up to 24 weeks, with the disease control rate in evaluable subjects of 38%. Exposure was proportional up to 100 mg and mean half-life was 141 h. The pharmacodynamic data revealed increases in innate immune cell activation, plasma IFNγ, TNFα, IP-10 and MCP-1.ConclusionPG545 demonstrated a tolerable safety profile, proportional PK, evidence of immune cell stimulation and disease control in some subjects. Taken together, these data support the proposed mechanism of action, which represents a promising approach for use in combination with existing therapies.

Abstract A18: The dual angiogenesis/heparanase inhibitor PG545, but not the tyrosine kinase inhibitor sorafenib, inhibits spontaneous metastasis in models of breast and lung cancer

PG545 is a fully synthetic heparan sulfate (HS) mimetic selected as the lead oncology candidate for formal preclinical development. PG545 inhibits key processes in tumor progression (a) neovascularization ‐ by interfering with growth factor binding and (b) metastasis ‐ presumably by inhibition of heparanase activity. PG545 was assessed for anti‐angiogenic activity in vivo and for antitumor and anti‐metastatic activity in the T41 breast cancer and the Lewis Lung Carcinoma (LL/2) models using the tyrosine kinase inhibitor sorafenib as an anti‐angiogenic reference compound. Both PG545 (daily or twice weekly) and sorafenib (daily) significantly reduced CD31 staining in the AngioSponge™ model. Twice weekly treatment with 25 mg/kg PG545, but not daily treatment with 60mg/kg sorafenib, significantly inhibited solid tumor growth in the T41 model. Moreover, PG545 significantly inhibited spontaneous lung metastases in a dose‐dependent manner, whereas sorafenib significantly increased the number of metastases. In the LL/2 model, once weekly treatment with PG545 at 20 mg/kg significantly reduced solid tumor growth to a similar extent as sorafenib while the 40mg/kg dose appeared more efficacious than sorafenib. A significant reduction in spontaneous lung metastases was again associated with PG545 following either a single injection or once weekly treatment while sorafenib had no appreciable effect on metastases. PG545 was well tolerated with no significant loss in bodyweight noted. Taken together, the data demonstrate that PG545 is an effective angiogenesis inhibitor with anti‐metastatic activity ‐ an envious property for an anti‐cancer compound, allaying recently publicized concerns that angiogenesis inhibitors and even chemotherapeutic agents may have the potential to aggravate metastatic development. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A18.

Structural and conformational studies of the heparan sulfate mimetic PI-88

The heparan sulfate mimetic PI-88 is a complex mixture of sulfated oligosaccharides with anti-metastatic and anti-angiogenic activity due to its potent inhibition of heparanase and heparan sulfate-dependent angiogenic growth factors. It was recently in Phase III clinical trials for postresection hepatocellular carcinoma. The major oligosaccharide constituents of PI-88 were prepared for the first time by sulfonation of individually purified phosphorylated oligosaccharides isolated from the PI-88 precursor. PI-88 and its components were subjected to detailed 1D and 2D NMR spectroscopic analysis. The spectra of the individual components greatly assisted the assignment of minor resonances in the 1H NMR spectrum of PI-88. The data also showed that the majority of the oligosaccharides in PI-88 are fully sulfated and that undersulfated species present are largely due to anomeric desulfation. The solution conformation of the phosphomannopentaose sulfate (major component) of PI-88 was then determined by a combination of molecular dynamics simulations and NOE measurements which may provide insights into its binding interactions with target proteins.