Abstract 658: Small molecule allosteric regulators of eIF4E activity target proteomic dysregulation and demonstrate potent antiproliferative activity in multiple myeloma models whilst sparing normal immune cells

Abstract

Abstract Multiple myeloma is characterized by significant dysregulation of protein translation. The eukaryotic translation initiation factor 4E (eIF4E), a rate determining element of oncogene translation, is highly expressed in multiple myeloma cells compared to normal plasma cells and is associated with enhanced levels of key oncogenic drivers such as MYC. We have developed potent small molecule allosteric regulators of eIF4E activity by aligning medicinal chemistry tools with patient directed pharmacology to optimize and identify orally bioavailable, potent compounds with in vivo activity. To identify sensitive cancer models and markers associated with response to PIC eIF4E regulators, we screened the 302-cell line Eurofins OncoPanel™, followed by gene expression profiling comparing the most and least sensitive cell lines and QIAGEN Ingenuity Pathway Analysis. Consistent with the role of eIF4E, we identified proteomic dysregulation as a marker of sensitivity to PIC eIF4E regulators. In addition, the multiple myeloma cell line MM.1R was amongst the most sensitive cell lines. Proteomic analysis of PIC eIF4E regulator treated MM.1R cells identified significant changes, both increases and decreases, in approximately 8% of the 7800 proteins detected by label free mass spectrometry. QIAGEN Ingenuity Pathway Analysis of significantly altered proteins identified enrichment of proteins involved in the G2/M checkpoint, cell cycle control of chromosomal replication, and DNA repair as well as protein translation, EIF4E regulation and mTOR signaling. PIC eIF4E regulators significantly decreased cell viability of both the steroid sensitive MM.1S and steroid resistant MM.1R multiple myeloma cell lines, which was associated with significantly reduced MYC protein levels. Consistent with earlier reported findings and the mechanistic impacts of PIC eIF4E regulators, reduced MYC expression was associated with a significant decrease in hyper-phosphorylated 4EBP1. In contrast to cancer cells, PIC eIF4E regulator treatment did not affect viability of B, T, NK and plasma cell populations in freshly isolated peripheral blood mononuclear cells (PBMCs) at exposures that cause significant cell death in multiple myeloma cells. Furthermore, CD4+ T-cells isolated from fresh PBMCs demonstrated proliferative responses following stimulation (ImmunoCult™) in the presence of PIC eIF4E regulators. The impact on key oncogenic drivers and potent antiproliferative activity in multiple myeloma models with minimal effects on normal immune cell populations suggests that targeting eIF4E activity with PIC allosteric eIF4E regulators could offer an attractive therapeutic strategy in multiple myeloma. Citation Format: Lisa-Marie Sturla, Xuemei Zhang, Yagmur Kan, Richard Gedrich, Katherine Bowdish, Christopher VanDeusen. Small molecule allosteric regulators of eIF4E activity target proteomic dysregulation and demonstrate potent antiproliferative activity in multiple myeloma models whilst sparing normal immune cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 658.