Abstract 2774: Anti-cancer activity of the tumor-selective, hypoxia-inducing, agent BNC105 in platinum resistant ovarian cancer

BNC105 is a small molecule that exerts anti-cancer activity through disruption of tubulin polymerization. BNC105 is unique in its ability to selectively block tumor blood flow resulting in hypoxia and cancer cell necrosis. A prodrug formulation, BNC105P, is under evaluation in a phase I/II clinical trial for metastatic renal cell carcinoma in combination with the mTOR inhibitor Everolimus. With the aim of expanding the development of BNC105 in the clinic, we investigated its activity in preclinical models of ovarian cancer. Despite modest improvements in patient outcomes as a result of surgery or platinum based chemotherapy, the majority of ovarian cancer patients relapse and die of their disease. There is a clear unmet medical need for more effective systemic therapy. The activity of BNC105 on the human ovarian carcinoma cell line A2780 and a derived cisplatin-resistant sub-line, A2780cis, was investigated using in vitro proliferation assays. BNC105 was a potent inhibitor of proliferation in both the A2780 and A2780cis cell lines with an IC50 of 0.3 and 0.1 nM respectively. In comparison, cisplatin and carboplatin were considerably less potent against A2780 with an IC50 of 330 nM and 7822 nM respectively. Both cisplatin and carboplatin were inactive against the sub-line A2780cis (IC50 >5 uM). BNC105 was also a potent disruptor of tumoral blood flow in A2780cis solid tumors grown subcutaneously in Balbc nu/nu mice. Tumors in mice treated with BNC105P exhibited a clear pattern of cavitation, with the center being completely deprived of blood perfusion. A small amount of blood perfusion was evident in the periphery of these tumors. In contrast, tumors obtained from animals treated with the vehicle control displayed dense blood perfusion throughout. Based on the observation of direct proliferative activity against A2780cis cells and the disruption of blood circulation in A2780cis tumors, it was reasoned that BNC105P treatment should induce tumor growth inhibition and increase survival in animals bearing A2780cis tumors. Mice bearing A2780cis solid tumors were treated with two weekly doses of BNC105P at 24mg/kg. For comparison purposes, separate animal groups bearing A2780cis tumors were treated with either cisplatin at 4mg/kg or carboplatin at 50mg/kg. Consistent with the lack of activity exhibited by platinum agents for these cells in vitro, there was no therapeutic benefit seen in animals treated with either platinum agent. In contrast, BNC105P treatment re