Neuroblastoma is the most common extracranial malignant solid tumor in children and drug resistance is a major reason for poor outcome of neuroblastoma. Thus, there is an urgent need for novel therapies. This proposal will pursue that goal by defining the role of. In our preliminary studies, we have found that DUSP26 is specifically overexpressed in majority of NB cell lines and tissue specimens. DUSP26 is required for neuroblastoma colony formation in vitro and promotes the resistance of neuroblastoma to doxorubicin- induced apoptosis by acting as a p53 phosphatase to inhibit p53 tumor suppressor function in neuroblastoma cells. Thus, DUSP26 acts as a p53 specific phosphatase to inhibit p53 functions in response to genotoxic stress in p53 wild-type neuroblastoma. Majority of neuroblastoma maintains functional p53 and apoptotic mechanisms which are suppressed in the majority of primary and relapsed cases. Thus, re-activation of p53 activity by inhibiting DUSP26 phosphatase activity represents an attractive therapeutic approach to this cancer. The central hypothesis of this work is that DUSP26 is an essential factor that regulates neuroblastoma growth, metastasis, and chemo-resistance. The proposed experiments will test this hypothesis by analyzing the biological role of DUSP26 in neuroblastoma development and determine whether DUSP26 inhibitor is able to inhibit neuroblastoma growth and enhance neuroblastoma chemo- sensitivity in an orthotopic mouse model.
The specific aims of this application are: 1) to determine whether DUSP26 knockdown alters neuroblastoma tumor growth in an orthotopic mouse model;2) to whether DUSP26 knockdown alters neuroblastoma tumor chemo-resistance in an orthotopic mouse model;3) to determine whether a novel DUSP26 inhibitor alters neuroblastoma tumor growth in an orthotopic mouse model;and 4) to determine the mechanism of DUSP26 function in neuroblastoma in response to doxorubicin treatment. The proposed project, if successful, will establish DUSP26 as a novel therapeutic target in neuroblastoma and a small molecule inhibitor against DUSP26 phosphatase activity may offer a therapeutic benefit for treating neuroblastoma patients. The long-term goal of this proposal is to improve the outcome of neuroblastoma patients by identifying and validating potential novel druggable targets for therapeutic intervention of this devastating disease in children.

Public Health Relevance

DUSP26, a member of Dual-Specificity Phosphatase family, is specifically overexpressed in majority of NB cell lines and tissue specimens, and is required for neuroblastoma colony formation in vitro, and promotes the resistance of neuroblastoma to doxorubicin-induced apoptosis by acting as a p53 phosphatase to inhibit p53 tumor suppressor function in neuroblastoma cells. In this research proposal, we aim to better understand the roles of DUSP26 in the neuroblastoma development and determine whether inhibition of DUSP26 activity is able to inhibit neuroblastoma growth and enhance neuroblastoma chemo-sensitivity in an orthotopic mouse model.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS072420-04
Application #
8625345
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fountain, Jane W
Project Start
2011-03-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
4
Fiscal Year
2014
Total Cost
$338,921
Indirect Cost
$122,358
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Wang, Yongfeng; Wang, Long; Guan, Shan et al. (2016) Novel ALK inhibitor AZD3463 inhibits neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosis. Sci Rep 6:19423
Li, Haoyu; Wang, Yongfeng; Chen, Zhenghu et al. (2016) Novel multiple tyrosine kinase inhibitor ponatinib inhibits bFGF-activated signaling in neuroblastoma cells and suppresses neuroblastoma growth in vivo. Oncotarget :
Guan, Shan; Zhao, Yanling; Lu, Jiaxiong et al. (2016) Second-generation proteasome inhibitor carfilzomib sensitizes neuroblastoma cells to doxorubicin-induced apoptosis. Oncotarget :
Chen, Zhenghu; Wang, Zhenyu; Pang, Jonathan C et al. (2016) Multiple CDK inhibitor dinaciclib suppresses neuroblastoma growth via inhibiting CDK2 and CDK9 activity. Sci Rep 6:29090
Li, Haoyu; Chen, Zhenghu; Hu, Ting et al. (2016) Novel proteasome inhibitor ixazomib sensitizes neuroblastoma cells to doxorubicin treatment. Sci Rep 6:34397
Zhang, Huiyuan; Dou, Jun; Yu, Yang et al. (2015) mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling. Apoptosis 20:50-62
Shi, Y; Ma, I T; Patel, R H et al. (2015) NSC-87877 inhibits DUSP26 function in neuroblastoma resulting in p53-mediated apoptosis. Cell Death Dis 6:e1841
Cheng, J; Fan, Y-H; Xu, X et al. (2014) A small-molecule inhibitor of UBE2N induces neuroblastoma cell death via activation of p53 and JNK pathways. Cell Death Dis 5:e1079
Fan, Yihui; Mao, Renfang; Yu, Yang et al. (2014) USP21 negatively regulates antiviral response by acting as a RIG-I deubiquitinase. J Exp Med 211:313-28
Fan, Yihui; Ge, Ningling; Wang, Xiaosong et al. (2014) Amplification and over-expression of MAP3K3 gene in human breast cancer promotes formation and survival of breast cancer cells. J Pathol 232:75-86

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