The long-term objective of this work is to determine the functional role of NEK2 in promoting cancer progression and to use this knowledge to develop novel therapies. The variability in survival of multiple myeloma patients ranges from only a few months to >10 years. We have previously shown that NEK2- expression is increased in multiple cancers including myeloma;higher levels of NEK2-expression induce cell rapid growth and resistance to multiple chemotherapeutics. This project builds upon our finding that when a specific gene (NEK2) that regulates the cell cycle is overexpressed, patients experience a clinically aggressive form and rapid death of myeloma and other cancers. We have made several striking discoveries supporting the hypothesis that NEK2 over-expression disrupts the normal cycle of tumor cell proliferation, resulting in poor survival for myeloma patients. Our goal to test the hypothesis will be accomplished by execution of three specific aims using both in vitro and in vivo models.
Aim1 : To examine the role of NEK2 in the development and progression of myeloma. We propose to evaluate whether myeloma cells with high-NEK2 expression are characterized with drug resistance in a large cohort of patients with myeloma at different stages;we will also test the growth and drug-resistance of primary myeloma cells with NEK2 high- or NEK2 low-expression in vitro and in vivo;we will introduce NEK2 into normal fibroblast cells and murine cancer-derived myeloma cell line that have low endogenous NEK2 expression, we will then analyze the effects of this alteration on cell transformation, cellular growth, and response to chemotherapeutic agents.
Aim 2 : to determine NEK2-mediated signaling pathways in cancer cell proliferation and survival. To achieve this goal, we will determine whether some cell growth related signaling pathways are required for NEK2-mediated cell growth and drug resistance in multiple myeloma. We will examine key substrates that directly interact with the NEK2 protein. Furthermore, gene expression profiling (GEP) will be performed on myeloma samples in remission and at relapse who also have GEP at baseline to identify genes that are regulated by NEK2 at different myeloma stages.
Aim 3 : to develop novel treatments based on targeting NEK2 or its signaling pathways. Through the screen of kinase inhibitor libraries, we have identified two small molecules that can specifically inhibit NEK2 kinase activity, and induce dramatic cancer cell death in vitro. We will use these molecules as a tool to explore their efficacy in killing myeloma cells in vivo. Inhibitors targeting these signaling pathways will be used alone or in combination with the current used chemotherapeutic drugs to evaluate their antimyeloma activities in vitro and in vivo.

Public Health Relevance

Multiple myeloma is the second most common hematological malignant. There is no effective therapy to cure this cancer. Thus, research is urgently needed to determine how this cancer develop and progress in order to design better therapies. In this grant, we propose studies to identify a novel protein target that may lead to develop better therapies for those aggressive myelomas.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA152105-05
Application #
8477011
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Arya, Suresh
Project Start
2010-07-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$285,690
Indirect Cost
$96,491
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Franqui-Machin, Reinaldo; Hao, Mu; Bai, Hua et al. (2018) Destabilizing NEK2 overcomes resistance to proteasome inhibition in multiple myeloma. J Clin Invest 128:2877-2893
Gu, Chunyan; Holman, Carol; Sompallae, Ramakrishna et al. (2018) Upregulation of FOXM1 in a subset of relapsed myeloma results in poor outcome. Blood Cancer J 8:22
Gu, Chunyan; Jing, Xuefang; Holman, Carol et al. (2018) Upregulation of FOXM1 leads to diminished drug sensitivity in myeloma. BMC Cancer 18:1152
Zhan, Xin; Yu, Wenjie; Franqui-Machin, Reinaldo et al. (2017) Alteration of mitochondrial biogenesis promotes disease progression in multiple myeloma. Oncotarget 8:111213-111224
Gu, Zhimin; Xia, Jiliang; Xu, Hongwei et al. (2017) NEK2 Promotes Aerobic Glycolysis in Multiple Myeloma Through Regulating Splicing of Pyruvate Kinase. J Hematol Oncol 10:17
Ramani, Vishnu C; Zhan, Fenghuang; He, Jianbo et al. (2016) Targeting heparanase overcomes chemoresistance and diminishes relapse in myeloma. Oncotarget 7:1598-607
Gu, C; Yang, Y; Sompallae, R et al. (2016) FOXM1 is a therapeutic target for high-risk multiple myeloma. Leukemia 30:873-82
Huang, Junwei; Zhou, Yi; Thomas, Gregory S et al. (2015) NEDD8 Inhibition Overcomes CKS1B-Induced Drug Resistance by Upregulation of p21 in Multiple Myeloma. Clin Cancer Res 21:5532-42
Salem, Kelley; McCormick, Michael L; Wendlandt, Erik et al. (2015) Copper-zinc superoxide dismutase-mediated redox regulation of bortezomib resistance in multiple myeloma. Redox Biol 4:23-33
Yang, Ye; Shi, Jumei; Gu, Zhimin et al. (2015) Bruton tyrosine kinase is a therapeutic target in stem-like cells from multiple myeloma. Cancer Res 75:594-604

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