Acute and chronic myeloid leukemias are responsible for approximately 15,000 deaths in the USA every year. These diseases frequently afflict people in the prime of their lives, and substantially less than half of all achieve long-term remission with current therapies, Most treatment options are both intense and toxic, requiring anti-neoplastic poly-chemotherapy, and, in some cases, therapy as radical as allogeneic hematopoietic cell transplantation, with its attendant risks. The overall goal of this proposal is to develop differentiation therapy to supplement the treatment regimens for this group of diseases. We will focus on the identification of the most effective analogs (deltanoids) of the physiological form of vitamin D, 1,25- dihydroxyvitamin D3 (1,25D3) administered at low concentrations to leukemia cells in culture to study alterations in gene expression and other changes in cell physiology. The deltanoids and 1,25D3 will also be administered in combination with nontoxic substances currently used as food preservatives or additives, or with potential for such use, to maximize the differentiation activity of the deltanoids. Established lines of leukemia as well as samples of leukemic cells freshly obtained from patients will be used for studies of cell differentiation. Insight into differentiation control will be obtained by examination of signaling pathways with particular attention to MAPK pathways and into cell cycle regulation by the expression of cyclin-dependent kinases as well as their activators and inhibitors. This will be accomplished by adding pharmacological agents, antisense oligonucleotides, transcription factor decoys, and transfected plasmid constructs to study the molecular consequences of these manipulations, which will be determined by immunoblotting, Northern analysis, RT-PCR, coimmunoprecipitation, and other standard techniques. Differentiating cells will be monitored by determination of surface makers as well as the activity of various kinases as and as their expression. The information obtained in basic studies will be utilized to guide development of a new generation of deltanoids and deltanoid combinations with co-inducers, while translational studies on leukemic cells ex vivo will serve to identify subgroups of myeloid leukemias most suitable for the initiation of clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA044722-17S1
Application #
7266460
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Ogunbiyi, Peter
Project Start
1987-06-01
Project End
2007-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
17
Fiscal Year
2006
Total Cost
$47,522
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Pathology
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
Wang, Xuening; Beute, William K; Harrison, Jonathan S et al. (2018) JNK1 as a signaling node in VDR-BRAF induction of cell death in AML. J Steroid Biochem Mol Biol 177:149-154
Zheng, Ruifang; Studzinski, George P (2017) Nuclear ERK5 inhibits progression of leukemic monocytes to macrophages by regulating the transcription factor PU.1 and heat shock protein HSP70. Leuk Lymphoma 58:1468-1480
Zheng, Ruifang; Studzinski, George P (2017) Optimal AraC-Cytotoxicity to AML Cells Requires ERK5 Activity. J Cell Biochem 118:1583-1589
Wang, Xuening; Harrison, Jonathan S; Studzinski, George P (2017) BRAF signals to pro-apoptotic BIM to enhance AraC cytotoxicity induced in AML cells by Vitamin D-based differentiation agents. J Steroid Biochem Mol Biol 173:139-147
Harrison, Jonathan S; Wang, Xuening; Studzinski, George P (2016) The role of VDR and BIM in potentiation of cytarabine-induced cell death in human AML blasts. Oncotarget 7:36447-36460
Wang, Xuening; Harrison, Jonathan S; Studzinski, George P (2016) Enhancement of arabinocytosine (AraC) toxicity to AML cells by a differentiation agent combination. J Steroid Biochem Mol Biol 164:72-78
Gocek, El?bieta; Studzinski, George P (2016) DNA Repair in Despair-Vitamin D Is Not Fair. J Cell Biochem 117:1733-44
Pesakhov, Stella; Nachliely, Matan; Barvish, Zeev et al. (2016) Cancer-selective cytotoxic Ca2+ overload in acute myeloid leukemia cells and attenuation of disease progression in mice by synergistically acting polyphenols curcumin and carnosic acid. Oncotarget 7:31847-61
Studzinski, George P; Harrison, Jonathan S; Wang, Xuening et al. (2015) Vitamin D Control of Hematopoietic Cell Differentiation and Leukemia. J Cell Biochem 116:1500-12
Wang, Xuening; Pesakhov, Stella; Harrison, Jonathan S et al. (2015) The MAPK ERK5, but not ERK1/2, inhibits the progression of monocytic phenotype to the functioning macrophage. Exp Cell Res 330:199-211

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