Abstract C200: Rapid nano-immunoassay for evaluation of mTOR pathway activation in acute myeloid leukemia.

Purpose To define the biology driving the aggressive nature of acute myeloid leukemia (AML) in elderly patients. Patients and Methods Clinically annotated microarray data from 425 patients with newly diagnosed de novo AML from two publicly available data sets were analyzed after age-specific cohorts (young ≤ 45 years, n = 175; elderly ≥ 55 years; n = 144) were prospectively identified. Gene expression analysis was conducted utilizing gene set enrichment analysis, and by applying previously defined and tested signature profiles reflecting dysregulation of oncogenic signaling pathways and altered tumor environment. Results Elderly AML patients as expected had worse overall survival and event-free survival compared with younger patients. Analysis of oncogenic pathways revealed that older patients had higher probability of RAS, Src, and tumor necrosis factor (TNF) pathway activation (all P < .0001). Hierarchical clustering revealed that younger patients with AML in cluster 2 had clinically worse survival, with high RAS, Src, and TNF pathway activation compared with patients in cluster 1. However, among elderly patients with AML, those in cluster 1 also demonstrated high RAS, Src, and TNF pathway activation but this did not translate into differences in survival. Conclusion AML in the elderly represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathway variations that contributes to poor survival. These insights should enable development and adjustments of clinically meaningful treatment strategies in the older patient population.

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STING Pathway Activation Stimulates Potent Immunity against Acute Myeloid Leukemia

Cell Reports ◽

10.1016/j.celrep.2016.05.023 ◽

2016 ◽

Vol 15 (11) ◽

pp. 2357-2366 ◽

Cited By ~ 61

Author(s):

Emily Curran ◽

Xiufen Chen ◽

Leticia Corrales ◽

Douglas E. Kline ◽

Thomas W. Dubensky ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Pathway Activation ◽

Sting Pathway ◽

Acute Myeloid

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Faculty Opinions recommendation of Clonal Selection with RAS Pathway Activation Mediates Secondary Clinical Resistance to Selective FLT3 Inhibition in Acute Myeloid Leukemia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.735760682.793564024 ◽

2019 ◽

Author(s):

Michael Weber

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Clonal Selection ◽

Ras Pathway ◽

Pathway Activation ◽

Clinical Resistance ◽

Acute Myeloid

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Dual PI3K/Akt/mTOR Pathway Inhibitor Potentiate Cytarabine Cytotoxicity For Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v122.21.1289.1289 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1289-1289

Author(s):

Eun Kyung Kim ◽

Hyoung Jin Kang ◽

Hyung Joon Kim ◽

Ji Won Lee ◽

Hyery Kim ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Cell Growth ◽

Cell Lines ◽

Myeloid Leukemia ◽

Signal Transmission ◽

Mtor Pathway ◽

Leukemic Cells ◽

Combination Regimen ◽

Dual Inhibitor ◽

Acute Myeloid

Abstract Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signal transduction pathway integrating signals from multiple receptor tyrosine kinases has been firmly established as a major determinant for cell growth, proliferation, and survival in a wide array of solid cancers. PI3K/Akt/mTOR pathway is frequently activated in acute myeloid leukemia (AML) cells and contributes to survival and drug-resistance of AML through various mechanisms. BEZ235 is one of the most promising dual inhibitor of PI3K and mTOR currently under clinical development in solid tumor area. In this study, the potential of BEZ235 was investigated as antileukemic agent using alone or with cytarabinearabinoside (AraC) as combination regimen. AML cell lines KG-1, MV 4-11, THP-1 and HL60 were treated with AraC, BEZ235 and combination regimen with various mixed ratio. BEZ235 effectively inhibited leukemic cell growth with similar range of half maximal inhibitory concentration (IC50) values among different cell lines. Apoptosis was induced gradually as BEZ235 concentration increased, but significant level of apoptosis was not shown even at higher concentration beyond IC50 value. Then, AraC-resistant MV4-11 and THP-1 cell lines were chosen to investigate interaction between BEZ235 and AraC. Using CalcuSyn software based on Chou and Talalay analysis, Combination Index (CI) value was calculated in each combination regimen. Moderate to strong synergism was shown and it was well maintained as combination ratio of AraC versus BEZ235 gradually decreased from 20:1 to 1,000:1. BEZ235 reduced resistance to AraC when it was added as combination regimen, and significance of combination effect changed according to AraC concentration. When antileukemic effect was compared among combination regimens with different schedules, synergism was maximized when BEZ235 was pretreated before AraC administration. This means BEZ235 sensitizes leukemic cells to apoptotic effect of AraC. Genetic alteration in PI3K/Akt/mTOR pathway is an attractive target to investigate and dual pathway inhibitor BEZ235 has potential to maximize AML treatment through sensitization of leukemic cells to conventional drug. The results of this experiment suggest the possibility of designing early clinical trials for the therapy - AraC administration after dual inhibitor BEZ administration. An effective control of a signal transmission system using innovate new drugs along with an accurate understanding of a signal transmission system which is the target of therapy will establish a foothold for the development of AML therapy. Disclosures: No relevant conflicts of interest to declare.

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