MLN0905, A Small Molecule PLK1 Inhibitor, Induces Anti-Tumor Responses in Human Models of Diffuse Large B-cell Lymphoma
Menée sur un modèle murin de lymphome diffus à grandes cellules B, cette étude évalue l'activité antitumorale d'un composé appelé MLN0905, une petite molécule inhibitrice de PLK1, seul et en combinaison avec du rituximab
Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin lymphomas, accounting for up to 30 percent 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 anti-tumor properties of MLN0905 in DLBCL xenograft models grown in mice. These studies indicate MLN0905 modulates the pharmacodynamic biomarker phospho-Histone H3 (pHisH3) in tumor tissue. The anti-tumor 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 anti-tumor activity on both a continuous (daily) and intermittent dosing schedule, underscoring dosing flexibility. The anti-tumor 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 anti-tumor effect and a synergistic survival advantage. Our findings indicate that PLK1 inhibition leads to pharmacodynamic pHisH3 modulation and significant anti-tumor activity in multiple DLBCL models. These data strongly suggest evaluating PLK1 inhibitors as DLBCL anti-cancer agents in the clinic.
http://mct.aacrjournals.org/content/early/2012/05/18/1535-7163.MCT-11-1036.abstract 2012