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 #
5R01CA152105-06
Application #
8677780
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
2014-06-01
Budget End
2015-05-31
Support Year
6
Fiscal Year
2014
Total Cost
$294,808
Indirect Cost
$99,571
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
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Zhou, W; Yang, Y; Gu, Z et al. (2014) ALDH1 activity identifies tumor-initiating cells and links to chromosomal instability signatures in multiple myeloma. Leukemia 28:1155-8
Meng, Lingyao; Carpenter, Kent; Mollard, Alexis et al. (2014) Inhibition of Nek2 by small molecules affects proteasome activity. Biomed Res Int 2014:273180
Gu, Zhimin; Zhou, Wen; Huang, Junwei et al. (2014) Nek2 is a novel regulator of B cell development and immunological response. Biomed Res Int 2014:621082
Zhou, Wen; Yang, Ye; Xia, Jiliang et al. (2013) NEK2 induces drug resistance mainly through activation of efflux drug pumps and is associated with poor prognosis in myeloma and other cancers. Cancer Cell 23:48-62
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