Abstract
PG545 is a clinically relevant heparan sulfate (HS) mimetic which, in addition to possessing anti-angiogenic properties, also acts as a heparanase inhibitor which may differentiate its mechanism(s) of action from approved angiogenesis inhibitors. The degradation of HS by heparanase has been strongly implicated in cell dissemination and the metastatic process. Thus, the anti-metastatic activity of PG545 has been linked to the enzymatic function of heparanase – the only endoglycosidase known to cleave HS, an important component of the extracellular matrix (ECM) which represents a potential avenue for therapeutic intervention for certain metastatic cancer indications. Recent concerns raised about the paucity of overall survival as an endpoint in mouse models of clinically relevant metastasis led us to examine the effect of PG545 on the progression of both primary tumor growth and the spontaneously metastasizing disease in the 4T1 syngeneic breast carcinoma model in a non-surgical and surgical (mastectomy) setting. PG545 significantly inhibited primary tumor growth but importantly also inhibited lung metastasis in treated mice, an effect not observed with the tyrosine kinase inhibitor sorafenib. Importantly, PG545 significantly enhanced overall survival compared to vehicle control and the sorafenib group, suggesting PG545’s inhibitory effect on heparanase is indeed a critical attribute to induce anti-metastatic activity. In addition to blocking a common angiogenic signalling pathway in tumor cells, the expression of heparanase in the primary tumor and lung was also significantly reduced by PG545 treatment. These results support the ongoing development of PG545 and highlight the potential utility in metastatic disease settings.
Highlights
Metastasis is the leading cause of cancer death [1]
PG545 treatment led to a significant inhibition of the primary tumor growth at all doses tested, producing TGI values of 29, 35 and 50% for 15, 20 and 25 mg/kg respectively (Figure 1C)
PG545 significantly suppressed the formation of surface lung metastases in a dose-dependent manner, producing inhibition rate (IR) values of 30, 66 and 95% for 15, 20 and 25 mg/kg PG545 respectively (Figure 1D)
Summary
Metastasis is the leading cause of cancer death [1]. According to the American Cancer Society, breast cancer is expected to account for 30% (230,480) of all new cancer cases among women [2]. 6–10% of patients have metastatic disease at the time of diagnosis and 30% who are initially diagnosed with earlierstage breast cancer will eventually develop recurrent advanced or metastatic disease [3]. The prognosis for these patients is poor, with an estimated 5-year survival of only 21% [4]. In addition to toxicity issues, the standard developmental approach to the treatment of micrometastatic disease assumes a progression from Phase I to Phase III trials in the metastatic setting, followed by a transition to large proof-ofconcept adjuvant trials. Only four were supported by results showing longer survival times [6], illustrating a clear need to better assess the anti-metastatic effect of cancer therapeutics and improve overall survival rates
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