Abstract 1461: The heparan sulfate mimetic PG545 potently inhibits spontaneous lung metastasis and significantly enhances overall survival in the 4T1 breast carcinoma model

Abstract

PG545 is a fully synthetic heparan sulfate (HS) mimetic entering Phase I clinical trials for advanced cancer. PG545 inhibits key processes in tumor progression (a) angiogenesis – by interfering with growth factor binding and (b) metastasis – by inhibition of heparanase activity. The syngeneic 4T1 breast carcinoma murine model is a well known model of spontaneous metastasis and PG545 was assessed for effects on primary tumour growth, metastatic development in lung and overall survival. PG545 and the tyrosine kinase inhibitor (TKI) sorafenib (used as a comparative antiangiogenic agent) were investigated for their effect on primary tumour growth and the number of lung metastases after treatment for two weeks. PG545 significantly inhibited solid tumour growth and potently inhibited the formation of lung metastases when administered on a twice-weekly dosing schedule (2xqw). Although sorafenib inhibited primary tumour growth to a similar extent as PG545, sorafenib significantly increased the number of lung metastases. In a separate study to investigate overall survival, mice had their primary tumours resected (mastectomy) on day 11 post-inoculation and treatment with PG545 (1xqw), sorafenib (1xqd) or cisplatin (1xqw) was administered for 55 days. Interim data on day 30 using satellite animals confirmed the potent antimetastatic activity of PG545 by enumeration of lung metastases. This reduction in metastasis correlated with overall survival in the PG545-treated mice in the main study which was significantly enhanced compared to vehicle control or sorafenib (which had a similar survival profile as control). PG545 also outperformed cisplatin. Mice culled due to clinical signs associated with disease progression correlated with histological assessment of metastatic burden in lung tissue. The antimetastatic effects of PG545 were confirmed by histological assessment at the end of the study on day 55, with very few metastases observed in PG545-treated mice. In conclusion, PG545 has potent anti-metastatic activity that would appear to differentiate it from other antiangiogenic therapies such as TKI's which have also been recently reported by other groups to aggravate metastatic development under certain circumstances. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1461. doi:10.1158/1538-7445.AM2011-1461