The overall goal of this proposal is to develop vitamin D-based therapeutic regimens to supplement the treatment, and design strategies for the prevention, of human acute myeloid leukemia (AML). Specifically, we will focus on the identification of analogs of the physiological form of vitamin D, 1,25- dihydroxyvitamin D3 (1,25D and analogs are collectively dubbed "deltanoids") which are the most effective when administered to leukemia cells in combination with Carnosic acid . We will study the alterations in gene expression, and other cellular changes that can be used as biomarkers of response to this treatment. AML cells ex vivo, freshly obtained from patients, and cells in established cultur will be used for studies of cell differentiation, resistance to differentiation, cell cycle arrest,and survival mechanisms in the presence of therapeutic toxic agents. The rationale is provided by numerous previous observations that deltanoids induce expression of genes which regulate monocytic differentiation but also can cause resistance to differentiation (Specific Aim 1), the differentiation-associated cell cycle arrest (Specific Aim 2), and cell survival changes dependent on microRNA32 and on signaling pathways that link the scaffold protein hKSR2 with NFkB complex(Specific Aim 3). Special attention will be given to deltanoids already approved for human administration the differentiation activity of which is highly enhanced by Carnosic acid. This project will be accomplished by a variety of approaches, including addition to cultured cells of pharmacological agents, antisense oligonucleotides, siRNAs, molecular decoys, and transfected plasmid constructs to study the molecular consequences of these manipulations, which will be determined by immunoblotting, quantitative RT-PCR, immunoprecipitation, and other molecular techniques. Differentiating cells will be monitored by determination of cell surface and molecular markers, as well as by the activity and the expression of various enzymes. The information obtained in basic studies will be utilized to guide development of Clinical Trials of deltanoids, and their combinations with the differentiation enhancer carnosic acid, while translational studies on leukemic cells ex vivo will serve to identify biomarkers of responsiveness to deltanoids and the recognition of subgroups of myeloid leukemias which will be the most suitable for the initiation of planned clinical trials.
Differentiation therapy, which depends on the activation of existing cellular programs rather than on toxic drugs to combat cancers and blood malignancies is already effective as the treatment of some of these diseases. We propose to develop it as treatment and prevention of blood malignancy known as acute myeloid leukemia which, although kills approximately 15,000 people in USA every year, is unlikely to receive attention for finding its cure from commercial sources. Therefore, acute myeloid leukemia can be considered an orphan disease and merits support from public sources for the development of novel therapy.
|Wang, Xuening; Pesakhov, Stella; Harrison, Jonathan S et al. (2014) ERK5 pathway regulates transcription factors important for monocytic differentiation of human myeloid leukemia cells. J Cell Physiol 229:856-67|
|Gocek, Elzbieta; Moulas, Anargyros N; Studzinski, George P (2014) Non-receptor protein tyrosine kinases signaling pathways in normal and cancer cells. Crit Rev Clin Lab Sci 51:125-37|
|Gocek, Elzbieta; Studzinski, George P (2012) Genes encoding transcription factors have self-control: how important is this for cell differentiation? Leuk Res 36:672-4|
|Chen-Deutsch, Xiangwen; Kutner, Andrzej; Harrison, Jonathan S et al. (2012) The pan-caspase inhibitor Q-VD-OPh has anti-leukemia effects and can interact with vitamin D analogs to increase HPK1 signaling in AML cells. Leuk Res 36:884-8|
|Wang, Xuening; Studzinski, George P (2011) Oncoprotein Cot1 represses kinase suppressors of Ras1/2 and 1,25-dihydroxyvitamin D3-induced differentiation of human acute myeloid leukemia cells. J Cell Physiol 226:1232-40|
|Gocek, Elzbieta; Wang, Xuening; Liu, Xiuping et al. (2011) MicroRNA-32 upregulation by 1,25-dihydroxyvitamin D3 in human myeloid leukemia cells leads to Bim targeting and inhibition of AraC-induced apoptosis. Cancer Res 71:6230-9|
|Bobilev, Irene; Novik, Victoria; Levi, Itai et al. (2011) The Nrf2 transcription factor is a positive regulator of myeloid differentiation of acute myeloid leukemia cells. Cancer Biol Ther 11:317-29|
|Zhang, Jing; Harrison, Jonathan S; Studzinski, George P (2011) Isoforms of p38MAPK gamma and delta contribute to differentiation of human AML cells induced by 1,25-dihydroxyvitamin D?. Exp Cell Res 317:117-30|
|Zhang, Jing; Harrison, Jonathan S; Uskokovic, Milan et al. (2010) Silibinin can induce differentiation as well as enhance vitamin D3-induced differentiation of human AML cells ex vivo and regulates the levels of differentiation-related transcription factors. Hematol Oncol 28:124-32|
|Hughes, Philip J; Marcinkowska, Ewa; Gocek, Elzbieta et al. (2010) Vitamin D3-driven signals for myeloid cell differentiation--implications for differentiation therapy. Leuk Res 34:553-65|
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