title: MLN0905, a small-molecule plk1 inhibitor, induces antitumor responses in human models of diffuse large B-cell lymphoma.
abstract: 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.
authors.affiliation: The Takeda Oncology Company, Cambridge, Massachusetts 02139, USA.
authors.forename: Judy Quiju
authors.initials: JQ
authors.lastname: Shi
authors.forename: Kerri
authors.initials: K
authors.lastname: Lasky
authors.forename: Vaishali
authors.initials: V
authors.lastname: Shinde
authors.forename: Bradley
authors.initials: B
authors.lastname: Stringer
authors.forename: Mark G
authors.initials: MG
authors.lastname: Qian
authors.forename: Debra
authors.initials: D
authors.lastname: Liao
authors.forename: Ray
authors.initials: R
authors.lastname: Liu
authors.forename: Denise
authors.initials: D
authors.lastname: Driscoll
authors.forename: Michelle Tighe
authors.initials: MT
authors.lastname: Nestor
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Amidon
authors.forename: Youlan
authors.initials: Y
authors.lastname: Rao
authors.forename: Matt O
authors.initials: MO
authors.lastname: Duffey
authors.forename: Mark G
authors.initials: MG
authors.lastname: Manfredi
authors.forename: Tricia J
authors.initials: TJ
authors.lastname: Vos
authors.forename: Natalie
authors.initials: N
authors.lastname: D' Amore
authors.forename: Marc L
authors.initials: ML
authors.lastname: Hyer
mesh_terms: D000284:Administration, Oral; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D001552:Benzazepines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005260:Female; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D000069283:Rituximab; D013871:Thiones / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D001552:Benzazepines; D018797:Cell Cycle Proteins; D006657:Histones; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000069283:Rituximab; D013871:Thiones; D000097869:Polo-Like Kinase 1; C570910:9-trifluoromethyl-2-((5-(3-(dimethylamino)propyl)-2-methylpyridin-3-yl)amino)-5,7-dihydro-6H-pyrimido(5,4-d)(1)benzazepine-6-thione