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NEK2 Over-expression Causes Drug Resistance in Myeloma

NEK2 过度表达导致骨髓瘤耐药

基本信息

批准号：
8099737
负责人：
FENGHUANG ZHAN
金额：
$ 30.09万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8099737
关键词：
Apoptosis Autologous Transplantation Biology Cancer Cell Growth Cancer cell line Cell Cycle Cell Cycle Deregulation Cell Cycle Regulation Cell Death Cell Line Cell Proliferation Cell Survival Cell physiology Cells Cessation of life Characteristics Chemicals Clinical Data Development Diagnosis Disease Disease Progression Disease remission Drug resistance Employee Strikes Enrollment Fibroblasts Gene Expression Profiling Genes Goals Grant Growth High Dose Chemotherapy Immunoprecipitation In Vitro Knowledge Lead Libraries Light MAP Kinase Gene MAPK14 gene MEKs Malignant - descriptor Malignant Neoplasms Mediating Minor Monitor Multiple Myeloma Mus Mutation Patients Pharmaceutical Preparations Phosphotransferases Population Protein-Serine-Threonine Kinases Proteins Protocols documentation Recurrent disease Relapse Research Residual Neoplasm Resistance Role Sampling Screening procedure Signal Pathway Signal Transduction Staging Testing Therapeutic Time Treatment Failure WNT Signaling Pathway Work base cancer cell cell growth cell transformation chemotherapeutic agent chemotherapy cohort design drug development effective therapy experience in vitro activity in vitro testing in vivo in vivo Model inhibitor/antagonist killings kinase inhibitor knock-down malignant phenotype mouse model neoplastic cell novel overexpression preclinical study protein protein interaction public health relevance rapid growth research study response small hairpin RNA small molecule tool translational study tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：