Abstract 3573: A small molecule PLK1 inhibitor, MLN0905, yields broad anti-tumor activity in human xenograft tumor models, and synergizes with taxane therapy

PLK1 is a serine/threonine mitotic kinase that plays a key role in mitotic cell cycle progression, and its over-expression has been linked to poor patient prognosis. We have discovered a potent and selective small molecule inhibitor of PLK1, MLN0905, which reduces cell viability and inhibits cell proliferation in a broad range of human tumor cells. We explored the pharmacokinetic, pharmacodynamic, and anti-tumor properties on MLN0905 in human xenograft models grown in rodents. MLN0905 rapidly and extensively distributed to xenograft tumor with a high tumor-to-plasma exposure ratio. In human xenograft tumor tissue, MLN0905 modulates the pharmacodynamic biomarker phospho-Histone H3 (in a dose dependent fashion), enabling us to track pathway modulation in vivo. MLN0905 demonstrated robust anti-tumor activity (partial and complete responses) in a variety of solid and hematological human xenograft models, including cancers derived from colon (HCT-116, HT29), NSCLC (Calu-6), Ovarian (SKOV3), and Lymphoma (OCI-LY19, OCI-LY10, and the primary lymphoma PHTX-22L). Significant anti-tumor activity was observed when dosing on either a continuous (daily) or intermittent schedule, underscoring the dosing flexibility with this compound. In the SKOV3 and Calu-6 xenograft models, MLN0905 yielded a synergistic anti-tumor response when combined with the standard of care therapy Taxane. This is the first report of a PLK1 inhibitor synergizing with taxane therapy in vivo. In summary, our findings indicate MLN0905 has good drug-like pharmacokinetic properties, modulates the biomarker phospho-Histone H3, and yields significant anti-tumor activity in multiple xenograft models. These preclinical data support further evaluating MLN0905 as a novel anti-cancer agent. 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 3573. doi:10.1158/1538-7445.AM2011-3573