Abstract 3695: The utility of plasma vascular endothelial growth factor and heparanase as pharmacodynamic markers following treatment with PG545, a heparan sulfate mimetic: preliminary evidence from preclinical and clinical settings
Authors: Dredge Keith , Hammond Edward , Winterhoff Boris , Giri Shailendra , Teoman Attila , Bampton Darryn , Millward Michael , Shridhar Viji 
Published: May 2015

Background: The heparan sulfate mimetic PG545 has been demonstrated to inhibit the function of vascular endothelial growth factor (VEGF) and heparanase (HPSE) in vitro whilst downregulating HPSE expression in tumor and metastatic tissue in vivo. Although there are reports of consistent drug-induced increases in plasma VEGF with VEGF inhibitors such as bevacizumab, similar data are lacking for HS mimetics. Given PG545's mechanism of action which involves inhibition of both angiogenesis and metastasis, the evaluation of plasma VEGF and HPSE may represent pharmacodynamic (PD) biomarkers for each of these key processes.

Materials and Methods: The levels of plasma VEGF and HPSE were measured using ELISA in samples from preclinical models of ovarian cancer (syngeneic ID8 and xenogeneic A2780 models) and a small cohort of patients (dosed with PG545 by the subcutaneous route) with advanced solid tumors from a Phase I clinical study. In tumor models, PG545 was administered once weekly by intravenous or intraperitoneal routes and efficacy was determined by quantifying tumor burden using the following methods: measurement of palpable solid tumors, abdominal circumference, ascites volume and/or by tracking cells using bioluminescent reporter imaging (depending on the model). In the A2780 model and the clinical samples, the pharmacokinetics of PG545 was also evaluated using LC-MS/MS, which ensured multiple samples to facilitate the measurement of VEGF and HPSE in plasma over the duration of the dosing interval following treatment with PG545.

Results: PG545 demonstrated potent antitumor and antimetastatic activity when administered once weekly via intravenous or intraperitoneal routes in preclinical studies. These studies also indicated that PG545 treatment led to increases in plasma VEGF and HPSE. Importantly, plasma samples from advanced cancer patients treated with PG545 also revealed increases in these PD markers with initial peaks often correlating with Cmax of PG545 but longer-term gradual increases also noted in some instances. We consider that these increases in plasma levels result from PG545 binding to, thereby inhibiting, VEGF and HPSE in the tumor microenvironment.

Conclusion: Given the questionable utility of single time point measures of plasma PD markers (including VEGF), these preliminary data suggest that kinetic profiling can reveal the previously undetermined dynamics of circulating VEGF and HPSE following treatment with PG545. Thus, the measurement of VEGF and HPSE appears to represent potential markers of pharmacodynamic activity. A new Phase I trial with intravenously-administered PG545 has recently commenced and should further clarify the potential utility of these basic PD biomarker responses in advanced cancer patients.

Citation Format: Keith Dredge, Edward Hammond, Boris Winterhoff, Shailendra Giri, Attila Teoman, Darryn Bampton, Michael Millward, Viji Shridhar. The utility of plasma vascular endothelial growth factor and heparanase as pharmacodynamic markers following treatment with PG545, a heparan sulfate mimetic: preliminary evidence from preclinical and clinical settings. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3695. doi:10.1158/1538-7445.AM2014-3695