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

Heparan 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.

The polyamine analog PG11047 potentiates the antitumor activity of cisplatin and bevacizumab in preclinical models of lung and prostate cancer.

PURPOSE: PG11047 is a polyamine analog currently in Phase I trials for advanced cancer as a monotherapy and in combination with a number of approved anti-cancer agents. The use of polyamines as a target for antiproliferative therapy is based on findings that cells synthesize polyamines excessively when induced to grow and that polyamine metabolism is frequently dysregulated in cancer. A selective polyamine transport system provides access for PG11047 into rapidly dividing cells to inhibit polyamine biosynthetic enzymes, to induce the polyamine catabolic enzymes spermidine/spermine N(1)-acetyltransferase (SSAT) and spermine oxidase (SMO) which could subsequently induce reactive oxygen species that contribute to tumor cell responses to PG11047, and to function as a polyamine with altered function when it binds to natural polyamine binding sites. The objective of the present study was to assess the antitumor effects of PG11047 alone and in combination with approved anti-cancer agents. METHODS: The antitumor efficacy of PG11047 as a single agent, and in combination with cisplatin and bevacizumab, was tested in models of lung (A549) and prostate (DU-145) cancer, respectively. RESULTS: PG11047 significantly inhibited tumor development in both lung and prostate cancer models when administered as a single agent. In the lung cancer model, PG11047 potentiated the antitumor effect of cisplatin. Although potent activity was observed with PG11047 and bevacizumab when administered as single agents in the prostate cancer model, the combination arm significantly enhanced antitumor activity compared with either agent alone. In all experiments, PG11047 was well tolerated with no adverse effects on bodyweight gain. CONCLUSIONS: The preclinical data support the rationale for the current Phase I trials which are assessing PG11047 as a monotherapy and in combination with a number of approved anti-cancer agents including cisplatin and bevacizumab.