Arsenic trioxide (ATO) is a Food and Drug Administration (FDA) approved therapy for a subtype of acute myeloid leukemia, acute promyelocytic leukemia (APL). There is also potential for clinical development of arsenic and/or other medicinal compounds for the treatment of other malignancies. However, to date arsenic has not shown significant clinical activity as a single agent outside of APL, likely due to the activation of negative feedback pathways that counteract its activity. The major goal of our research group is to investigate the mechanisms of action of arsenic in myeloid leukemias, understand the negative feedback pathways activate by arsenic and identify agents that can be combined with it to enhance clinical outcomes in patients. In this proposal we seek to investigate the role of AMPK in the anti-leukemic effects of arsenic and how that contributes to the induction of mTOR as a negative feedback loop as well as in the induction of autophagy. It was previously shown in our laboratory that during treatment of leukemia cells with arsenic there is activation of the mTOR pathway through an unknown mechanism. We have preliminary data to suggest that arsenic directly binds to AMPK and inhibits its activity. Because AMPK is a direct negative regulator of mTOR, we propose that this is an important mechanism for activation of the mTOR pathway by arsenic.
In Aim 1 we will investigate how arsenic affects AMPK structure and function. We also propose that arsenic through AMPK inhibition leads to induction of autophagy through the VPS34/Beclin/UVRAG complex since AMPK can negative regulate VSP34.
In Aim 2 we will combine arsenic with AMPK activators to investigate the role of AMPK signaling in the induction of anti-leukemic effects of arsenic in vivo in a xenograft mouse model of acute myeloid leukemia (AML). Altogether, this work should define the mechanisms by which arsenic activates negative feedback pathways and may lead to the development of novel agents for the treatment of leukemias.
Currently there is a need for new therapies as the 5 year overall survival for acute myeloid leukemia is 5 - 55% depending on the risk group which is based on cytogenetic abnormalities. Many of the therapeutic agents investigated in this study are or will be tested in clinical trials in multiple subtypes of cancer. This proposal seeks to investigate in a preclinical setting what agents can be combined to enhance clinical outcomes in acute myeloid leukemia patients and therefore could be used as combinatorial strategies in future therapeutic regimens.
|Curi, Dany A; Beauchamp, Elspeth M; Blyth, Gavin T et al. (2015) Pre-clinical evidence of PIM kinase inhibitor activity in BCR-ABL1 unmutated and mutated Philadelphia chromosome-positive (Ph+) leukemias. Oncotarget 6:33206-16|
|Colamonici, Marco; Blyth, Gavin; Saleiro, Diana et al. (2015) Dual targeting of acute myeloid leukemia progenitors by catalytic mTOR inhibition and blockade of the p110? subunit of PI3 kinase. Oncotarget 6:8062-70|
|Beauchamp, Elspeth M; Kosciuczuk, Ewa M; Serrano, Ruth et al. (2015) Direct binding of arsenic trioxide to AMPK and generation of inhibitory effects on acute myeloid leukemia precursors. Mol Cancer Ther 14:202-12|
|Sassano, Antonella; Mavrommatis, Evangelos; Arslan, Ahmet Dirim et al. (2015) Human Schlafen 5 (SLFN5) Is a Regulator of Motility and Invasiveness of Renal Cell Carcinoma Cells. Mol Cell Biol 35:2684-98|