Small Molecule Therapeutics Novel Treatment for Mantle Cell Lymphoma Including Therapy-Resistant Tumor by NF-kB and mTOR Dual-Targeting Approach

Mantle cell lymphoma (MCL) is one of the most aggressive B-cell non-Hodgkin lymphomas with a median survival of approximately five years. Currently, there is no curative therapy available for refractory MCL because of relapse from therapy-resistant tumor cells. TheNF-kBandmTORpathways are constitutively active in refractoryMCL leading to increasedproliferation and survival. Targeting thesepathways is an ideal strategy to improve therapy for refractory MCL. Therefore, we investigated the in vitro and in vivo antilymphoma activity and associated molecular mechanism of action of a novel compound, 13-197, a quinoxaline analog that specifically perturbs IkB kinase (IKK) b, a key regulator of the NF-kB pathway. 13-197 decreased the proliferation and induced apoptosis inMCL cells including therapy-resistant cells comparedwith control cells. Furthermore, we observed downregulation of IkBa phosphorylation and inhibition of NF-kB nuclear translocation by 13-197 in MCL cells. In addition, NF-kB–regulated genes such as cyclin D1, Bcl-XL, and Mcl-1 were downregulated in 13-197–treated cells. In addition, 13-197 inhibited the phosphorylation of S6K and 4E-BP1, the downstreammolecules of mTOR pathway that are also activated in refractory MCL. Further, 13-197 reduced the tumor burden in vivo in the kidney, liver, and lungs of therapy-resistant MCL-bearing nonobese diabetic severe-combined immunodeficient (NOD/SCID)mice comparedwith vehicle-treatedmice; indeed, 13-197 significantly increased the survival of MCL-transplanted mice. Together, results suggest that 13-197 as a single agent disrupts the NF-kB and mTOR pathways leading to suppression of proliferation and increased apoptosis inmalignantMCL cells including reduction in tumor burden inmice.Mol Cancer Ther; 12(10); 1–12. 2013 AACR