Abstract 662: Evaluation of the anti-cancer effects of the tumor selective vascular disruption agent BNC105 in preclinical renal cancer models

Abstract

Abstract The disruption of blood vessels that feed tumors represents one of the most promising therapeutic strategies for treating cancer. BNC105 is a tubulin targeting dual acting vascular disruption agent with cytotoxic ability in solid tumors. A prodrug formulation, BNC105P, is under evaluation in phase II clinical trials for malignant mesothelioma and metastatic renal cell carcinoma as a 10min IV infusion. We have conducted a number of preclinical evaluations that provide a strong rationale for combining BNC105P treatment with agents that target mTOR signalling. BNC105 activity operates through the selective disruption of tumor blood vessels. Over 95% of blood flow is disrupted in tumors grown in xenograft animal models using human cancer cell lines representing a number of different cancer types, including breast, lung, colon, brain and mesothelioma. In the renal cancer setting we evaluated the anti-cancer effects of BNC105 in a Caki-1 xenograft model and a syngeneic murine renal cancer orthotopic model. Animals carrying Caki-1 solid tumors were treated with a single dose of BNC105P. Disruption of blood flow within the tumors was observed as early as 3 hr post-treatment. Similarly, blood flow disruption was seen in mice carrying solid tumors orthotopically inoculated in the kidney capsule using the RENCA mouse renal cancer cell line. Interestingly, BNC105P treatment also caused blood flow disruption in lung metastatic lesions seen in a number of the animals orthotopically inoculated with RENCA. The vasculature in non-cancerous portions of the kidney and all normal tissues examined, remained intact. Tumor re-vascularisation following BNC105P treatment was observed 2 days following administration. Immunohistochemical and Western blot analyses in BNC105P treated tumors revealed that a number of proteins involved in the mTOR signalling pathway exhibit expression changes consistent with activation of this pathway possibly a result of BNC105P induced tumor hypoxia. Up-regulation in phosphorylated mTOR, Hif1a and down-regulation of phosphorylated 4EBP1 were observed. The consequences of targeting mTOR in combination with BNC105P are currently under investigation in these preclinical models. 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 662. doi:10.1158/1538-7445.AM2011-662