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 #
1R01NS072420-01
Application #
8026739
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fountain, Jane W
Project Start
2011-03-01
Project End
2015-02-28
Budget Start
2011-03-01
Budget End
2012-02-28
Support Year
1
Fiscal Year
2011
Total Cost
$342,344
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Mao, Xinfang; Chen, Zhenghu; Zhao, Yanling et al. (2017) Novel multi-targeted ErbB family inhibitor afatinib blocks EGF-induced signaling and induces apoptosis in neuroblastoma. Oncotarget 8:1555-1568
Bieerkehazhi, Shayahati; Chen, Zhenghu; Zhao, Yanling et al. (2017) Novel Src/Abl tyrosine kinase inhibitor bosutinib suppresses neuroblastoma growth via inhibiting Src/Abl signaling. Oncotarget 8:1469-1480
Guan, Shan; Lu, Jiaxiong; Zhao, Yanling et al. (2017) TAK1 inhibitor 5Z-7-oxozeaenol sensitizes cervical cancer to doxorubicin-induced apoptosis. Oncotarget 8:33666-33675
Li, Haoyu; Wang, Yongfeng; Chen, Zhenghu et al. (2017) Novel multiple tyrosine kinase inhibitor ponatinib inhibits bFGF-activated signaling in neuroblastoma cells and suppresses neuroblastoma growth in vivo. Oncotarget 8:5874-5884
Chen, Zhenghu; Wang, Long; Yao, Dayong et al. (2016) Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis. Sci Rep 6:38011
Lu, Jiaxiong; Guan, Shan; Zhao, Yanling et al. (2016) Novel MDM2 inhibitor SAR405838 (MI-773) induces p53-mediated apoptosis in neuroblastoma. Oncotarget 7:82757-82769
Guan, Shan; Zhao, Yanling; Lu, Jiaxiong et al. (2016) Second-generation proteasome inhibitor carfilzomib sensitizes neuroblastoma cells to doxorubicin-induced apoptosis. Oncotarget 7:75914-75925
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
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

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