Abstract A7: The heparan sulfate mimetic PG545 as a monotherapy or in combination with the standard-of-care agents paclitaxel or carboplatin inhibits solid tumor progression in two murine models of ovarian cancer.

Abstract

Abstract PG545 is a fully synthetic heparan sulfate (HS) mimetic currently being assessed by subcutaneous administration in Phase I clinical trials for advanced cancer patients. PG545 inhibits the enzymatic activity of heparanase, angiogenesis, solid tumor growth and spontaneous metastases in different tumor types. As a role for tumor angiogenesis emerged in the development of ovarian cancer, the number the clinical investigations using avascular therapies have increased in recent years. Moreover, given the fact that ovarian cancers can metastasize by multiple routes, the dual antiangiogenic and antimetastatic activity of PG545 may offer a promising approach to treat ovarian cancer patients. Standard treatment with PG545 involved a loading and maintenance dosing regimen of 20 mg/kg followed by weekly injections of 10 mg/kg as previously reported. In these studies the antitumor effect of weekly dosing with PG545, both as a monotherapy and in combination with standard-of-care agents, was investigated. In the first study, mice bearing A2780 tumors were treated with PG545 alone, paclitaxel alone (15 mg/kg, qw) or in combination of both compounds. Treatment with PG545 reduced tumor growth (TGI = 42%) compared to vehicle control and was more effective than paclitaxel alone (TGI = 11%). In combination, PG545 and paclitaxel significantly reduced tumor volume (TGI = 61%) compared to vehicle control. In a second model, mice bearing SKOV3 tumors received PG545, carboplatin (60 mg/kg) or in combination. Treatment with PG545 significantly inhibited tumor growth (TGI = 40%) compared to vehicle control, almost equivalent to the effect of carboplatin monotherapy (TGI = 41%). The combination regimen further impacted tumor growth, showing a significant effect by day 19 of treatment (TGI = 71% versus the vehicle control and the monotherapy groups). In conclusion, PG545 demonstrates antitumor activity as a monotherapy in ovarian cancer models which can be substantially enhanced using combination regimens with current standard-of-care agents such as paclitaxel and carboplatin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A7.