Abstract 358: Inhibition of AKT phosphorylation in acute myeloid leukemia by ISC 4

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease with percent remission of 35-40% for younger patients and 5-15% for older patients and a survival of 5-10 months if left untreated. This emphasizes the urgent unmet need for new therapeutics in AML. The activation of PI3K/AKT signaling pathway plays an important role in cellular survival, proliferation and regulation of apoptosis in cancer cells including leukemia. Recent studies showed that activation of AKT may correlate with poor prognosis in AML. Furthermore, mutations such as FLT3-ITD in the PI3K-AKT pathway causing constitutive activation of AKT, are very common in AML, therefore, it remains as an important target for AML treatment. Phenylbutyl isoselenocyanate (ISC-4), a small drug-like molecule that is developed by our group through optimization of naturally occurring isothiocyanates, targets the P13K-AKT pathway in melanoma and other gastrointestinal malignancies. In this study, we demonstrated potent activity of ISC-4 against AML. We tested the cytotoxicity of ISC-4 in various human AML cell lines (n=6) and in samples collected from AML patients (n=8). AML cell lines exhibited dose-dependent sensitivity to ISC-4 in the low micromolar range (IC50: 2-5 uM) as did most primary AML cases. Western blotting showed a dose dependent decrease in AKT phosphorylation in MV-4-11 and AML-OCI3 cell lines, and lead to an increase in cleaved PARP levels, indicating the induction of apoptosis. Furthermore, ISC-4 treatment reduced the clonogenicity of primary AML cells at relatively low concentrations. Future studies will aim to further develop ISC-4 as a single agent and in combination with anti-leukemic agents and demonstrate the preclinical efficacy in AML animal models including AML patient derived xenografts (PDXs). Together, these data demonstrates the therapeutic potential of ISC-4 that can be a promising drug candidate for further development as a novel therapy for AML. Citation Format: Shreya Thakur, Charyguly Annageldiyev, Srinivasa Ramisetti, Trupti Patel, Saumya Iyer, Pavan Dhanyamraju, Shantu Amiin, Arun Sharma, David Claxton, Arati Sharma. Inhibition of AKT phosphorylation in acute myeloid leukemia by ISC 4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 358.