Abstract 643: Therapeutically targeting eIF4E overexpressing breast cancers destined for early metastatic relapse

Abstract Pathways downstream of PI3K/AKT/mTOR that regulate protein translation, ribosome biogenesis, transcription, metabolism and autophagy are essential to the formation and progression of many human cancers as evidenced by the clinical approval of such selective mTOR inhibitors as temsirolimus (CCI-779, Wyeth) and everolimus (RAD-001, Novartis). However, clinical limitations to the effective use of mTOR inhibitors include the lack of validated tumor marker(s) predictive of mTOR inhibitor responsiveness, mTOR inhibitor release of S6 kinase-mediated negative feedback resulting in secondary activation of PI3K/AKT, and transcriptional upregulation of the downstream effector eIF4E. Using breast cancer cell lines (MCF7, MCF7/HER2, BT474, SKBr3, MDA231) showing varying sensitivity to RAD-001 (IC50 values for MTT viability @ 5 d from &amp;lt;0.2 nM to &amp;gt;20 nM), we observe marked suppression of phos-p70S6K and secondary phos-AKT activation, with variable suppression of phosSer65-4E-BP1 and downstream translation of eIF4E-dependent survival and proliferation proteins (e.g. cyclin D1). To circumvent these limitations of mTOR inhibitors, we are directly targeting eIF4E, as this m7G 5'cap-binding initiator of translation has been shown to be oncogenic and appears elevated in up to 30% of malignancies, with breast cancer ratios of eIF4E/4E-BP1&amp;gt;1 indicating that mTOR inhibition may not be able to reverse eIF4E-driven breast tumorigenesis. Moreover, initial clinical studies of two different eIF4E inhibitors, an investigational antisense oligonucleotide (LY2275796; Isis/Lilly) that reduces eIF4E levels and the approved antiviral ribavirin that physically mimics the m7G 5’ cap structure, indicate that selective in vivo inhibition of eIF4E can be achieved with little or no host toxicity. Our in vitro comparison of phenotypically diverse human breast cancer models indicates that RAD-001 and ribavirin differentially inhibit growth and suppress phos-AKT and cyclin D1 levels in a phenotype-dependent manner. To evaluate the potential of this eIF4E drug target as a prognostic biomarker, 621 node-negative and adjuvant naïve breast cancer cases with expression microarray data and distant metastasis-free survival (DMFS) clinical annotation were curated from public databases, and the normalized eIF4E transcript levels were dichotomized (high, low) for Kaplan-Meier outcome analyses. Increased eIF4E transcript levels are significantly associated with worse DMFS, but only for estrogen receptor (ER)-positive breast cancer cases (n = 400, log rank p = 0.04). These preclinical and clinical findings provide new rationale for pursuing the breast cancer therapeutic potential of targeting eIF4E, especially in eIF4E mRNA overexpressing ER-positive breast cancer cases most likely to experience metastatic relapse within 5 years of diagnosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 643.

Topic: PI3K/AKT/mTOR signaling in cancer
Subfield: Molecular Biology
Field: Biochemistry, Genetics and Molecular Biology
Domain: Life Sciences