Abstract
Abstract Mantle cell lymphoma (MCL) is recognized as a distinct subtype of B-cell lymphoma and it is characterized by cyclin D1 over-expression, which is caused by t(11;14)(q13;q32) translocation and unregulated cell cycle progression driven by increased cyclin-dependent kinase (CDK) activity. Accordingly, small inhibitors for CDKs represent a potential therapy for MCL. We are investigating a selective small molecule CDK inhibitor, AZD5438, which has nanomolar ranges of IC50 for cyclin E/CDK2, cyclin A/CDK2, cyclin B1/CDK1 and cyclin T/CDK9 and comparing its anti-tumor effects with a pan-CDK inhibitor, Flavopiridol. We hypothesize that inhibition of CDK1/2 by AZD5438 may lead to G1/S and G2 arrest, and therefore inhibit tumor cell proliferation and induce apoptosis in MCL. In Jeko-1 MCL cell lines, AZD5438 has shown both time- and dose-dependent inhibition of cell proliferation, inhibition of the phosphorylation of CDK substrates, and cell cycle arrest in G1 phase. The EC50 for AZD 5438 is 1μM as determined by inhibition of cell viability. We further developed an in vivo MCL xenograft assay: first, to guide the optimization of dosage and dosing schedule for clinical use; and second, to explore the selectivity and potency of this drug using phospho-histone H3 (Ser10) flow cytometry and phosopho-Rb (Ser249/Thr252) immunoblotting as our drug efficacy monitoring system. Recently we have established GFP transduced Jeko-1 cells and inoculated them into 8 to 12 week-old, immune-compromised NOD SCID mice. Investigations of AZD5438 drug dosage in this xenograft model are ongoing. Ultimately, this project is aimed at improving the treatment for MCL patients and reducing the toxic responses to the standard chemotherapeutic regimes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3890.
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