Abstract 4115: BNC420 is a novel VEGFR3 selective inhibitor, which unlike the pan-VEGFR inhibitor Sunitinib, suppresses lymphatic metastasis in a model of metastatic melanoma

Abstract

Abstract The dissemination of cancer cells through the lymphatic system is a well-known route of metastasis. Studies have implicated the hypoxic tumor microenvironment as an instigator of tumor cell invasion and metastatic spread. The use of angiogenesis inhibitors targeting VEGFR2 has been reported in preclinical models to augment metastasis through increased hypoxia within the tumor microenvironment. We have sought to identify a selective VEGFR3 targeting compound that will inhibit metastatic spread through lymphatic dissemination without the concomitant hypoxia induced metastasis effect associated with VEGFR2 targeting. BNC420 is a novel small molecule inhibitor of VEGFR3 phosphorylation that displays significant selectivity over VEGFR2. In phosphorylation detection ELISA based assays BNC420 exhibited a 25 fold greater potency for VEGFR3 over VEGFR2 with IC50 of 30nM and 744nM respectively. We investigated the activity of BNC420 and the pan-VEGFR inhibitor Sunitinib in the B16F10 murine melanoma model. This model involves the intradermal administration of B16F10 melanoma cells in the mouse ear resulting in the formation of a primary lesion, metastatic satellite lesions (in-transit) and regional lymph node metastasis. While Sunitinib slowed the growth of the primary lesion, as expected, it did not inhibit the development of lymph node metastasis and appeared to enhance the development of in-transit satellite lesions by 38% compared to its corresponding vehicle control. In contrast, only 20% of animals treated with BNC420 exhibited in-transit lesions compared to 53% in the corresponding vehicle control. Furthermore, a 50% reduction in the number of metastasis to the draining lymph nodes was seen in BNC420 treated animals. The lymph node metastatic lesions were significantly smaller compared to control and in some instances only detected under microscopic examination. Melanoma lesions in animals treated with BNC420 were devoid of peritumoral lymphatic vessels. These results demonstrate that selective inhibition of VEGFR3 utilising the novel small molecule BNC420 effectively inhibits the development of both in-transit metastatic lesions and lymph node metastasis while being unencumbered by the pro-metastatic effects that can accompany VEGFR2 inhibition through the induction of tumor hypoxia. Citation Format: Annabell Leske, Tina Lavranos, Donna Beaumont, Chloe Brown, Darham Paul, Daniel Inglis, Michaela Scherer, Andrew Harvey, Gabriel Kremmidiotis. BNC420 is a novel VEGFR3 selective inhibitor, which unlike the pan-VEGFR inhibitor Sunitinib, suppresses lymphatic metastasis in a model of metastatic melanoma. [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 4115. doi:10.1158/1538-7445.AM2015-4115