Abstract 4486: Antiangiogenic platinum through glycan targeting

Abstract

Abstract Heparanase is an endo-β-D-glucuronidase that cleaves heparan sulfate glycosaminoglycans (HS-GAGs) in the extracellular matrix and basement membrane. Cancer cells that aberrantly express heparanase potentiate tumor progression, invasion and metastasis in two distinct ways; (1) cleavage of HS-GAGs releases growth-factors to directly activate growth receptors and (2) degradation of the heparan sulfate structural component of the extracellular matrix (ECM) allows metastatic spread of cancer cells. Recently, we determined that accumulation and cytotoxicity of polynuclear platinum compounds (PPCs), including the Phase II clinical trial compound, BBR3464 (+4), are dependent on the presence of cell-surface GAGs. Here, we demonstrate that high affinity PPC-GAG binding provides a new approach to glycan-based targeting by protection against enzymatic cleavage by heparanase. It was determined by NMR spectroscopy, that PPCs, especially the higher charged compound, TriplatinNC (+8), inhibit heparanase cleavage of the oligosaccharide, Fondaparineaux. Further, using the human umbilical primary cell line, HUVEC, it was determined that PPCs reduce heparanase cleavage of the GAG-bound growth factor, bFGF, from ECM. The end result of inhibition of heparanase cleavage is a reduction in tumor invasion and angiogenesis. Using the matrigel invasion assay, we show that sub-cytotoxic doses of PPCs, but not cisplatin, reduces serum-induced invasion of HCT116 cells through basement membrane. In an ex vivo rat aorta model, PPCs exhibit antiangiogenesis activity, measured by the inhibition of new blood vessel growth sprouting from the original aortic ring. Together, these encouraging results support the potential to combine anti-metastatic and cytotoxic activity in the development of dual-function platinum-based drugs. Citation Format: Erica J. Peterson, Susan J. Berners-Price, Anna Bezos, Lisa Bohlman, Samantha J. Katner, A. Gerard Daniel, Chih-Wei Chang, Mark von Itzstein, Christopher R. Parish, Nicholas P. Farrell. Antiangiogenic platinum through glycan targeting. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4486. doi:10.1158/1538-7445.AM2015-4486