Abstract 1942: Activity of lenalidomide in vitro and in vivo models of bortezomib-resistant mantle cell lymphoma involving the modulation of c-myc/p27 axis

Abstract

Abstract Mantle cell lymphoma (MCL) is an aggressive B lymphoid neoplasm genetically characterized by the t(11;14)(q13;q32) leading to the overexpression of cyclin D1. As a consequence of its poor responses to conventional chemotherapy and relatively short patient survival, new therapeutic strategies are required. Despite the promising introduction of the proteasome inhibitor bortezomib in the clinical practice, not all the patients respond and relapse frequently occurres after initial response. When comparing the behavior of both bortezomib-resistant and bortezomib-sensitive cell lines in a xenotransplant mouse model, we observed an increased tumorigenecity of bortezomib-resistant cells in vivo, suggesting a major capacity of these tumors to interact with lymphoid microenvironment. As the immunomoduladory drug lenalidomide has been shown to modulate tumor-stroma interaction in several B cell malignancies, we assessed the activity in vitro and in vivo of this agent either alone or combined with the proteasome inhibitor in both bortezomib-resistant and bortezomib-sensitive samples. Lenalidomide single agent was found to exert modest antitumoral activity in 2/10 MCL cell lines, corresponding to those cells with either primary or acquired resistance to the proteasome inhibitor. Conversely, mice bearing bortezomib-resistant tumors and treated for 3 weeks with a 10-50 mg/kg/day regimen of lenalidomide, showed a 30 to 45% reduction in tumor burden when compared to vehicle-treated group (p<0.05). The corresponding biopsies harbored several hallmarks of lenalidomide activity in malignant B cells such as CD80 and CD40L upregulation, together with a remarkable decrease in mitotic index, c-myc down-regulation, p27 cytosolic accumulation and caspase-3 processing. Similarly, bortezomib-resistant MCL cell lines treated for 72h with 1 microM lenalidomide showed lower c-myc levels, as well as p27 accumulation, caspase-3/7 activity and apparition of hypodiploid cells. When combined to bortezomib therapy (0.15 mg/kg, twice a week), lenalidomide induced a 37% and a 66% inhibition of tumor growth when compared to lenalidomide and vehicle groups, respectively (p=0.02). In accordance, lenalidomide showed synergistic effect in vitro with bortezomib in co-culture system associating the MCL cell line Jeko-1 to the dendritic-like cells BDCM, by modifying the secretion pattern of these latest. Altogether, these results suggest that single agent lenalidomide is preferentially effective in MCL cases resistant to bortezomib, by targeting c-myc-driven tumorigenesis. Additionally, lenalidomide may overcome the protection offered by lymphoid tumor microenvironment toward bortezomib treatment, thus warranting a promising clinical activity of lenalidomide-bortezomib combination in MCL cases refractory to bortezomib. 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 1942. doi:1538-7445.AM2012-1942