Abstract 5408: The novel retinamide VNLG-152, which targets translation by promoting degradation of MAPK-interacting kinases, has preferential activity in acute myeloid leukemia with FLT3-ITD

Abstract

Abstract Purpose: Acute myeloid leukemia (AML) with internal tandem duplication (ITD) mutations of the fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase has a poor prognosis, with short disease-free survival following both chemotherapy and allogeneic hematopoietic stem cell transplantation. FLT3 inhibitors are active, but their activity is limited and transient. New treatments and approaches are needed. The novel retinamide (NR) VNLG-152, targets translation by promoting degradation of MAPK-interacting kinases (Mnks), thereby inhibiting phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), a downstream target of FLT3-ITD. eIF4E aids in translation by recruiting ribosomes to mRNA, a process that is upregulated in AML with FLT3-ITD. The association of the eIF4E protein complex is the rate- limiting step in translation initiation. We characterized the effects of VNLG-152 in AML cell lines and patient samples with FLT3-ITD and with wild-type FLT3. Methods: Cell lines studied included human MV4-11 and MOLM-14, with endogenous FLT3-ITD expression, HL60 and U937, with wild-type FLT3, and Ba/F3-ITD and Ba/F3-WT, which are murine Ba/F3 cells transfected with human FLT3-ITD and wild-type FLT3, respectively. Cytotoxicity was measured in a WST-1 colorimetric assay, proliferation by carboxyfluorescein diacetate succinimidyl ester (CFSE) staining, and apoptosis by Annexin V-FITC and propidium iodide labeling, measured by flow cytometry. AML patient samples obtained on an IRB-approved protocol were studied in cytotoxicity assays. Results: VNLG-152 was cytotoxic to the human FLT3-ITD AML cell lines MV4-11 and MOLM-14 with low micromolar IC50 concentrations, while IC50 concentrations were greater than 10 μM in the wild-type FLT3 AML cell lines HL60 and U937. IC50s in Ba/F3-ITD and Ba/F3-WT cells were 3.6 μM (95% CI, 3.0-3.9 μM) and 5.7 μM (95% CI, 5.0-6.4 μM), respectively. The cellular effects of VNLG-152 were evaluated further in Ba/F3-ITD cells. Concentration-dependent slowing of proliferation was seen at low micromolar concentrations, while concentration-dependent pro-apoptotic effects occurred at higher concentrations. VNLG-152 was also cytotoxic to blasts isolated from FLT3-ITD AML patient samples at IC50 concentrations <1 μM, whereas its IC50 concentrations in blasts from AML patient samples with wild-type FLT3 were > 5 μM. Conclusion: We conclude that the novel Mnk degrading agent VNLG-152 is active in AML with FLT3-ITD. Subsequent work will examine combinations with FLT3 inhibitors and with chemotherapy drugs in this prognostically unfavorable AML subtype. Citation Format: Sheetal Karne, Karthika Natarajan, Senthilmurugan Ramalingam, Lalji K. Gediya, Vincent C.O. Njar, Maria R. Baer. The novel retinamide VNLG-152, which targets translation by promoting degradation of MAPK-interacting kinases, has preferential activity in acute myeloid leukemia with FLT3-ITD. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5408. doi:10.1158/1538-7445.AM2015-5408