Abstract LB-384: Elevated eIF4E phosphorylation is associated with advanced malignancy and decreased patient survival and can be therapeutically inhibited by a novel, orally bio-available Mnk inhibitor

Abstract

Abstract Malignant progression & reduced patient survival have been linked to increased function of eukaryotic translation initiation factor 4E (eIF4E), which selectively enables translation of potent growth/survival factors & oncoproteins (e.g. c-myc, VEGF, cyclin D1, Mcl-1). Recent reports have shown that the oncogenic activity of eIF4E is critically dependent on the activity of MNK kinases (Map kinase interacting kinases 1 and 2). Furthermore, increased eIF4E phosphorylation, a consequence of Mnk activity, has been linked to advanced cancers, including head & neck & non-small cell lung cancers. Herein, by immunohistochemical analysis of 133 prostatic tissues from 76 men, we report that eIF4E phosphorylation is significantly elevated in human prostate cancers (CaP) in relation to disease progression. eIF4E phosphorylation is associated with advanced disease (trend analysis, p < 0.0001) & is increased significantly in both low grade (Gleason score ≤ 6) & high grade (Gleason score ≥ 7) CaP vs. adjacent normal prostate tissue (BPH) (p < 0.02 and p < 0.0001, respectively). Elevated eIF4E phosphorylation in invasive prostate cancer CaP is related to significantly reduced patient survival (p = 0.0216) & increased risk of death from CaP (hazard ratio = 2.729). These data, along with data in experimental models implicating MNK activity in cellular transformation, indicate that therapeutic targeting of MNK activity may provide an attractive anti-cancer therapeutic strategy. Indeed, we now report the identification of a novel, small molecule Mnk inhibitor with IC50 values of 116 nm & 11nm against Mnk 1 & Mnk 2, respectively. This Mnk inhibitor suppresses eIF4E phosphorylation in a dose & time-dependent manner in a wide array of cancer cell lines, including melanomas, colorectal cancers, lymphomas, leukemias & prostate cancers. In HCT116 colon cancer, treatment with the Mnk inhibitor suppresses eIF4E phosphorylation and diminishes expression of the pro-survival factor Mcl-1. Mnk inhibitor treatment also suppresses cellular proliferation, induces apoptosis & dramatically diminishes soft agar colonization. Further, oral administration of this inhibitor suppresses eIF4E phosphorylation in normal mouse tissues and in xenografted human cancers within 30 minutes, lasting at least 4 hours in tumor tissue. Once daily (20mg/kg) or twice daily (10mg/kg) oral dosing significantly suppresses subcutaneous xenograft tumor growth. Moreover, oral dosing reduces dramatically the number and size of pulmonary metastases formed in mice injected intravenously with B16 melanoma cells & treated 12 consecutive days starting 1 day after cell injection. These data demonstrate the utility of this novel Mnk inhibitor in probing Mnk function in vitro & in vivo and highlight the potential anti-cancer therapeutic utility of suppressing Mnk function. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-384. doi:10.1158/1538-7445.AM2011-LB-384