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PDF file, 42KB, Pharmacokinetic profiles of plasma and OCI-LY19-Luc tumor tissue in mice treated with a single oral dose of MLN0905.

PDF file, 45KB, MLN0905 yields significant anti-tumor responses in mice bearing subcutaneous OCI LY-19-Luc tumors.

PDF file, 43KB, Evaluating pHisH3 in OCI LY-19-Luc and OCI LY-10 cells following MLN0905 treatment.

Diffuse large B-cell lymphoma (DLBCL) is the most common of the non–Hodgkin lymphomas, accounting for up to 30% of all newly diagnosed lymphoma cases. Current treatment options for this disease are effective, but not always curative; therefore, experimental therapies continue to be investigated. We have discovered an experimental, potent, and selective small-molecule inhibitor of PLK1, MLN0905, which inhibits cell proliferation in a broad range of human tumor cells including DLBCL cell lines. In our report, we explored the pharmacokinetic, pharmacodynamic, and antitumor properties of MLN0905 in DLBCL xenograft models grown in mice. These studies indicate that MLN0905 modulates the pharmacodynamic biomarker phosphorylated histone H3 (pHisH3) in tumor tissue. The antitumor activity of MLN0905 was evaluated in three human subcutaneous DLBCL xenograft models, OCI LY-10, OCI LY-19, and PHTX-22L (primary lymphoma). In each model, MLN0905 yielded significant antitumor activity on both a continuous (daily) and intermittent dosing schedule, underscoring dosing flexibility. The antitumor activity of MLN0905 was also evaluated in a disseminated xenograft (OCI LY-19) model to better mimic human DLBCL disease. In the disseminated model, MLN0905 induced a highly significant survival advantage. Finally, MLN0905 was combined with a standard-of-care agent, rituximab, in the disseminated OCI LY-19 xenograft model. Combining rituximab and MLN0905 provided both a synergistic antitumor effect and a synergistic survival advantage. Our findings indicate that PLK1 inhibition leads to pharmacodynamic pHisH3 modulation and significant antitumor activity in multiple DLBCL models. These data strongly suggest evaluating PLK1 inhibitors as DLBCL anticancer agents in the clinic. Mol Cancer Ther; 11(9); 2045–53. ©2012 AACR.

PDF file, 59KB.

PDF file, 44KB, Evaluating cell viability in DLBCL cell lines following MLN0905 treatment.

PDF file, 53KB, MLN0905 yields significant anti-tumor responses in mice bearing subcutaneous OCI LY-10 tumors.

PDF file, 48KB, Plasma and OCI LY-19-Luc tumor pharmacokinetic parameters following a single oral dose of MLN0905 in CB-17 SCID mice.