The Investigational Aurora A Kinase Inhibitor Alisertib Exhibits Broad Activity in Preclinical Models of T-Cell Lymphoma and Is Highly Synergistic with Romidepsin

摘要: Aurora A kinase (AAK), a serine-threonine protein kinase, regulates mitotic entry, spindle formation, and cytokinesis. Alisertib is selective AAK investigational inhibitor with demonstrated clinical activity in acute myeloid leukemia, peripheral T-cell lymphoma (PTCL), DLBCL other hematologic malignancies. Herein we demonstrate the potent cytotoxicity apoptotic effects of alisertib panel T-cell-derived cell-lines (TCL) (CTCL, HTLV+, T-ALL) B-cell (DLBCL-ABC, DLBCL-GCB, MCL) alone combination romidepsin. Single agent concentration time effect relationships were generated for 8 TCL, 4 (2 ABC, 2 GCB) MCL cell-lines. The mean IC 50 TCL was 350 nM (range 100-1000nM) lines (DLBCL, 200 20-300 nM) at 48 hours, measured by growth inhibition. In all cell evaluated, there consistent 2-log fold decrease values 72 demonstrating exquisite impact on effect. Combination studies evaluating synergy performed testing schedule, concentration, relationships. combinatorial experiment to identify potential synergistic interactions found no pralatrexate or proteasome inhibitors, but revealed Interestingly, simultaneous exposure combined romidepsin their 10 , 20, 30 marked only not lymphomas. best observed hours coefficients ranging from 0.2 0.7. This interaction restricted cell-lines, benefit lines. (Table 1) We further evaluated this through lapse (0-72hr) live imaging that treatment H9, CTCL line, led failure cytokinesis leading apoptosis. Evidence apoptosis confirmed cell-line, H9 HH after increased Puma, Caspase 3 PARP cleavage, decreased BCL-xL BCL2 expression; suggesting death apoptotic. AnnexinV/propridium iodide via FACS analysis induction addition, cycle following 24 hour as single combination. produced G2/M arrest while both agents induced polyploidy (up 8N). finding may also complement increase versus agents. Furthermore, preliminary results an in-vivo xenograft amongst when compared control cohort cohorts. These data support observation produces broad single-agent models demonstrates Interestingly TCL. Mechanistic better understand are ongoing. It hypothesized synergistically inhibit activation stat-3, inhibition cellular proliferation c-MYC. [1] 1=additive; 1= subadditive Disclosures Amengual: Acetylon Pharmaceuticals: Research Funding. O9Connor: Millennium Consultancy; Celgene : Consultancy.