Abstract 3543: Anti-tumor activity of the vascular disruption agent BNC105 in models of mesothelioma and lung cancer
Authors: Leske Annabell F. , Beaumont Donna M. , Lavranos Tina C. , Gasic Jelena , Kremmidiotis Gabriel 
Published: June 2012

Abstract
BNC105 is a small molecule that exerts anti-cancer activity through disruption of tubulin polymerisation. BNC105 is unique in its ability to selectively target activated endothelial cells usually found in tumor blood vessels. A prodrug formulation, BNC105P, is under evaluation in phase II clinical trials for mesothelioma and renal cancer as a 10min IV infusion. In a xenograft model utilizing the human lung cancer cell line Calu-6, BNC105P caused significant tumor vascular disruption following a single dose. Similar levels of vascular disruption were observed in xenograft tumors arising from subcutaneous injection of the human mesothelioma cell line MSTO-211H. In addition, near complete vascular disruption was observed in lung metastatic lesions in a syngeneic kidney orthotopic model using the murine renal cancer cell line RENCA. We conducted preclinical evaluations that provide evidence of the activity of BNC105 in animal models of mesothelioma and lung cancer as a monotherapy and in combination with current standard of care therapies. Tumor doubling time, tumor growth delay and animal survival were assessed. Animal survival end points were defined in terms of tumor volume, with animals bearing tumors &gt;2000mm3 being euthanised. Cisplatin and Gemcitabine are currently used in first line treatment of non small cell lung cancer. The effect of BNC105P treatment as a monotherapy or in combination with these two agents was investigated in a xenograft model of lung cancer. Mice carrying subcutaneous Calu-6 tumors were treated with two BNC105P doses 1 week apart as a monotherapy or in combination with Cisplatin or Gemcitabine. Combined therapy with BNC105P and Cisplatin resulted in reduced tumor growth. Tumor doubling time for the combination was 27 days, whereas the doubling time for treatment with BNC105P or Cisplatin monotherapies was 20 days and 10 days respectively. The tumor growth delay seen with the combination was 17 days greater compared to cisplatin alone with all animals in the combination arm showing tumor regression during this period. Significant increases in survival were also observed with 100% of animals in the combination group surviving, compared to 33% in the BNC105P and 0% in the Cisplatin treatment groups. In combination with Gemcitabine, BNC105P conferred tumor growth delay that was 3 days greater than BNC105P monotherapy and 17 days greater than Gemcitabine monotherapy. The survival rate in the combination group was 55% compared to 33 % in BNC105P monotherapy group and 0% in the Gemcitabine only group. Pemetrexed in combination with Cisplatin is the currently approved first line treatment for mesothelioma. The therapeutic potential of BNC105P was compared to Cisplatin and Pemetrexed in a xenograft model of the human mesothelioma cell line MSTO-211H. Compared to control, BNC105P increased survival rate by 40% with Cisplatin and Pemetrexed monotherapies increasing survival rates by 20%.
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 3543. doi:10.1158/1538-7445.AM2011-3543