Abstract B38: Targeting FOXM1 in multiple myeloma

Abstract

Abstract Unprecedented progress in our understanding of the biologic and molecular genetic underpinnings of multiple myeloma (MM) has recently led to the development of novel targeted therapeutic agents, including proteasome inhibitors, immunomodulatory drugs, CS1-binging antibody, and histone deacetylase inhibitors, which have produced tangible, evidence-based benefits for patients with MM. Nonetheless, the overall outcome remains grim, due in large part to limitations in treating high-risk MM. We recently determined that the level of FOXM1 mRNA expression is of prognostic significance for myeloma patients, as both event-free survival and overall survival were reduced in cases exhibiting high FOXM1 expression. Forty-six of 351 myeloma patients (13.1%) had elevated FOXM1 message, with the majority (29/46, 63%) residing in the MAF/MAFB and proliferation high-risk molecular subgroups. Upregulation of FOXM1 was also observed in patients deemed high-risk using the 70-gene signature as a metric. These results suggest that upregulation of FOXM1 is a feature of high-risk MM, leading to the hypothesis that up-regulation of FOXM1 contributes to increased MM aggressiveness. To evaluate whether targeting FOXM1 results in reduced growth and survival of myeloma cells, MM cell lines exhibiting high levels of FOXM1 were found to have low micromolar sensitivity to treatment with thiostrepton or siomycin A — two thiazole antibiotics known to inhibit FOXM1 activity. Because of known off-target effects of these inhibitors, we are confirming the results using short-hairpin RNA. Our data suggest that developing effective therapeutic strategies against high-risk MM should include consideration of FOXM1 as a new target. Citation Format: Van S. Tompkins, Zhimin Gu, Hongwei Xu, Guido Tricot, Fenghuang Zhan, Siegfried Janz. Targeting FOXM1 in multiple myeloma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B38.