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 #
5R01NS072420-03
Application #
8423394
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fountain, Jane W
Project Start
2011-03-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
3
Fiscal Year
2013
Total Cost
$330,362
Indirect Cost
$119,268
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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; 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
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, Y-H; Cheng, J; Vasudevan, S A et al. (2013) USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis. Cell Death Dis 4:e867
Ernst, Andreas; Avvakumov, George; Tong, Jiefei et al. (2013) A strategy for modulation of enzymes in the ubiquitin system. Science 339:590-5
Liang, Li; Fan, Yihui; Cheng, Jin et al. (2013) TAK1 ubiquitination regulates doxorubicin-induced NF-*B activation. Cell Signal 25:247-54
Fan, Yihui; Cheng, Jin; Vasudevan, Sanjeev A et al. (2013) TAK1 inhibitor 5Z-7-oxozeaenol sensitizes neuroblastoma to chemotherapy. Apoptosis 18:1224-34
An, Lei; Jia, Wei; Yu, Yang et al. (2013) Lys63-linked polyubiquitination of BRAF at lysine 578 is required for BRAF-mediated signaling. Sci Rep 3:2344
Fan, Yihui; Mao, Renfang; Yang, Jianhua (2013) NF-?B and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell 4:176-85
Fan, Yihui; Shi, Yi; Liu, Shangfeng et al. (2012) Lys48-linked TAK1 polyubiquitination at lysine-72 downregulates TNF*-induced NF-*B activation via mediating TAK1 degradation. Cell Signal 24:1381-9