Abstract
Abstract 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.
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