Abstract 1920: Small molecule inhibitor of polo-like kinase 1 (Plk1) causes significant melanoma growth delay and regression in vivo

Abstract

Abstract Melanoma is an aggressive skin cancer that rapidly metastasizes to become lethal, if not diagnosed early. An analysis of the Surveillance, Epidemiology, and End Results (SEER) program has suggested that the age-adjusted annual incidence of melanoma, both for young men and women, has increased over the past 20 years. In 2011, it is projected that over 70,000 new cases of melanoma will be diagnosed with nearly 9,000 cases resulting in death. Current preventive and treatment approaches have not been able to effectively manage this neoplasm. Therefore, new mechanism- and target- based approaches are urgently needed. Better understanding of the genetic control of cellular proliferation and cell division may provide the basis for the rational design of specific therapeutics for the management of cancers, including melanoma. We have previously demonstrated that the mitotic regulator Polo-like kinase 1 (Plk1) is over-expressed in clinical melanoma and a targeted depletion of Plk1 through lentiviral shRNA or a small-molecule inhibitor causes mitotic catastrophe and induction of apoptosis in human melanoma cells (J Invest Dermatol 129: 2843-53, 2009). In this study, we assessed the effect of BI6727, a second generation Plk1 specific small molecule inhibitor, in vivo in athymic nu/nu nude mice implanted with human melanoma cells. A375 cells (1x106 cells) were implanted in athymic nude by subcutaneous injection on the right flanks. The tumors were allowed to grow and the mice bearing established tumors (>100 mm3) were randomized into 3 groups (containing 12 mice each). The mice were treated with BI6727 at two doses (10 mg/kg or 25 mg/kg) or a vehicle control via tail vein injections twice weekly. Our data demonstrates that in BI6727 treated animals, the rate of tumor growth (to reach to a 1000 mm3 target volume) was significantly delayed. We also found that BI6727 at 25 mg/kg resulted in a near complete tumor regression. The observed tumor regression was stable for several days following discontinuation of treatment, after which, the tumors started growing again. Additionally, we found that BI6727 caused i) a significant inhibition of cell growth and viability, and ii) induction of apoptosis in multiple melanoma cell lines. Based on this study, we suggest that Plk1 is a druggable target for melanoma and pharmacological inhibitors of Plk1 could be clinically useful in melanoma therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1920. doi:1538-7445.AM2012-1920