Abstract 4705: Dual targeting of epigenetic pathways and NF-kappaB in diffuse large B-cell lymphoma

Abstract

Abstract INTRODUCTION: Current immunochemotherapy can cure approximately two-thirds of patients with diffuse large B cell lymphoma (DLBCL), the most common type of non-Hodgkin's lymphoma. Drugs that selectively target specific mechanisms of pathogenesis to which the disease is known to be addicted, offer a unique opportunity to intervene in the natural history of the disease, and may hold the key to future breakthroughs in treating DLBCL. While several unique pathogenetic events have been recently identified in driving lymphomagenesis, two potentially interrelated events contributing to the underlying molecular pathogenesis of DLBCL have come to light. The first involves constitutive activation of NF-kappaB, as noted by Rosenwald and colleagues in their identification of the activated B-cell (ABC) subtype of DLBCL, while the second involves dysregulation of the protein acetylation-deacetylation balance due to either inactivating mutations of histone acetyltransferases (HATs) like p300 and CBP, or overexpression of histone deacetylases (HDACs). HATs and HDACs operate epigenetic pathways to modulate gene expression and to control the activity of important oncoproteins such as Bcl6 through posttranslational modification. While Bcl6 and NF-kappaB are known to be closely associated with the pathogenesis of GCB (germinal center B-cell) and ABC subtypes of DLBCL respectively, it has become clear that many ABC lymphomas can have dysregulation of Bcl6, and many cases of GCB DLBCL can have dysregulation of NF-kappaB. Therefore, strategies oriented toward modulation of these biological traits could offer a unique opportunity to treat DLBCL at its molecular roots, potentially sensitizing them to traditional chemotherapy approaches. RESULTS: We have conducted pharmacological and molecular studies of a novel IKKbeta inhibitor, LY2409881, in DLBCL cell lines. We found that LY2409881 specifically inhibited the activation of NF-kappaB and increased apoptosis, and inhibited both ABC and GCB cells that are addicted to NF-kappaB, with moderate potentcy. Furthermore, LY2409881 demonstrated marked anti-lymphoma synergism with HDAC inhibitors; the synergism varied significantly in a cell line and HDAC inhibitor-dependent manner. The discrete patterns of synergism among different HDAC inhibitors with LY2409881 were not solely attributable to acetylation of p65/RelA mediated by HDAC inhibitors, as these inhibitors all stimulated binding of p65/RelA to its target DNA. We will determine the mechanism of the drug: drug synergism by investigating whether knocking down HDAC molecules in lymphoma cells make them hypersensitive to IKK inhibitors. We are using xenograft lymphoma models in mice to confirm the in vivo activity of LY2409881, as a single agent and in combination with HDAC inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4705. doi:1538-7445.AM2012-4705