Neuroblastoma (NB) continues to be the most common extracranial solid tumor in children. The majority of high-risk NB patients show an initial response to therapy but ultimately relapse, suggesting that acquired drug resistance or selection of therapy-resistant cells occurs with chemotherapy treatment. This presents a major obstacle for treatment. Understanding the molecular mechanisms that mediate resistance to chemotherapy and targeting key molecules in this pathway are pivotal for curing this disease. NF-?B activation is frequently encountered in tumor cells and it is believed to be one of the mechanisms of cancer chemotherapy resistance. Chemotherapeutic agents and radiation therapy can activate NF-?B. TAK1 is a pivotal kinase intermediate for IKK and MAPK activations, as well as IL-6 gene expression in response to multiple stimuli. Recently, interactions between tumor and inflammatory cells have been reported to contribute to the clinical metastatic NB phenotype. A galectin-3-dependent pathway in NB cells has been found to upregulate IL-6 in the microenvironment of human NB. IL-6 expression in stromal cells and macrophages promotes NB proliferation in tumor microenvironment. TAK1 mediates NF-?B and MAPK activations in response to genotoxic stresses. Given that NF-?B and MAPK activations are two major survival signals, we hypothesize that inhibition of TAK1 activation may disrupt the balance between cell-death and cell-survival, and sensitize cells to chemotherapy resulting in cell death. Furthermore, TAK1 inhibition in stromal cells and tumor-associated macrophages may block tumor-induced IL-6 expression and disrupt their functional interaction with NB cells in tumor microenvironment. In our preliminary studies, we have found that TAK1 inhibition by a small molecule inhibitor (5Z-7-oxozeaenol) significantly enhances the sensitivity of NB cells to chemotherapy in vitro and in vivo. The central hypothesis of this work is that TAK1 plays an important role in chemoresistance of NB by mediating the interaction of NB tumor cells with stromal cells and tumor-associated macrophages in the tumor microenvironment. The proposed experiments will test this hypothesis by using an orthotopic and TH-MYCN transgenic mouse models to analyze the effect of TAK1 inhibitor on tumor chemoresistance and tumor microenvironment.
The specific aims for this application are: 1) to determine whether TAK1 inhibitor sensitizes NB cells to chemotherapy in both orthotopic xenograft and TH-MYCN transgenic mouse models of NB;2) to determine the effect of TAK1 inhibition on the interaction of NB cells and tumor microenvironment in these models. The proposed project, will establish TAK1 as a therapeutic target in NB. Furthermore, this small molecule inhibitor of TAK1 kinase may serve as a potential adjunct in the treatment of high-risk NB patients. The long-term goal of this proposal is to identify and validate potential druggable enzymatic targets for therapeutic intervention of this devastating disease in children.

Public Health Relevance

TAK1, a member of MAP kinase kinase family, plays an essential role in mediating NF-?B and MAPK activation and IL-6 gene expression in response to inflammatory stimuli and genotoxic stresses. In our preliminary studies, by using a panel of NB cell lines including a chemoresistant NB cell line, we have found that TAK1 inhibition by its small molecule inhibitor (5Z-7-oxozeaenol) significantly enhances the sensitivity of NB cells to chemotherapy-induced cell-death in vitro and in vivo. In this research proposal, we aim to determine whether inhibition of TAK1 activity is able to sensitize neuroblastoma to chemotherapies and disrupt the functional interaction of tumor cells with other types of cells via inhibition of IL-6 gene expression in tumor microenvironment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS085467-02
Application #
8733777
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Fountain, Jane W
Project Start
2013-09-15
Project End
2015-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
2
Fiscal Year
2014
Total Cost
$233,590
Indirect Cost
$85,090
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Lu, Jiaxiong; Guan, Shan; Zhao, Yanling et al. (2017) The second-generation ALK inhibitor alectinib effectively induces apoptosis in human neuroblastoma cells and inhibits tumor growth in a TH-MYCN transgenic neuroblastoma mouse model. Cancer Lett 400:61-68
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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