DUSP26: A Novel Therapeutic Target in Neuroblastoma

DUSP26：神经母细胞瘤的新治疗靶点

• 批准号: 8227975
• 负责人: JIANHUA YANG
• 金额: $ 34.23万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8227975
• 关键词: Apoptosis; Apoptotic; Biological; Cell Death; Cell Line; Child; Development; Disease; Doxorubicin; Drug resistance; Family; Gene Expression; Genotoxic Stress; Goals; Growth; Human; In Vitro; Luciferases; Malignant - descriptor; Malignant Neoplasms; Mass Spectrum Analysis; Mus; Neoplasm Metastasis; Neuroblastoma; Outcome; Patients; Phosphoric Monoester Hydrolases; Protein p53; Proteins; Relapse; Reporter Genes; Research Proposals; Resistance; Role; Solid Neoplasm; Specificity; Specimen; Testing; Therapeutic; Therapeutic Intervention; Tissues; Work; improved; inhibitor/antagonist; member; mouse model; neuroblastoma cell; new therapeutic target; novel; overexpression; public health relevance; research study; response; small molecule; tumor; tumor growth; tumor xenograft

DESCRIPTION (provided by applicant): 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.

描述（申请人提供）：神经母细胞瘤是儿童最常见的颅外恶性实体瘤，耐药性是神经母细胞瘤预后不良的主要原因。因此，迫切需要新的疗法。该提案将通过定义角色来实现这一目标。在我们的初步研究中，我们发现DUSP26在大多数NB细胞系和组织标本中特异性过度表达。 DUSP26 是体外神经母细胞瘤集落形成所必需的，并通过充当 p53 磷酸酶抑制神经母细胞瘤细胞中的 p53 肿瘤抑制功能，促进神经母细胞瘤对阿霉素诱导的细胞凋亡的抵抗。因此，DUSP26 作为 p53 特异性磷酸酶，在 p53 野生型神经母细胞瘤中抑制 p53 响应基因毒性应激的功能。大多数神经母细胞瘤维持功能性 p53 和细胞凋亡机制，这些机制在大多数原发性和复发性病例中受到抑制。因此，通过抑制 DUSP26 磷酸酶活性来重新激活 p53 活性代表了治疗这种癌症的一种有吸引力的方法。 这项工作的中心假设是 DUSP26 是调节神经母细胞瘤生长、转移和化疗耐药的重要因素。拟议的实验将通过分析 DUSP26 在神经母细胞瘤发展中的生物学作用来检验这一假设，并确定 DUSP26 抑制剂是否能够在原位小鼠模型中抑制神经母细胞瘤生长并增强神经母细胞瘤化学敏感性。 本申请的具体目的是：1) 确定 DUSP26 敲低是否会改变原位小鼠模型中的神经母细胞瘤肿瘤生长； 2) DUSP26敲低是否会改变原位小鼠模型中的神经母细胞瘤化疗耐药性； 3) 确定新型 DUSP26 抑制剂是否会改变原位小鼠模型中的神经母细胞瘤肿瘤生长； 4) 确定 DUSP26 在神经母细胞瘤中响应阿霉素治疗的功能机制。 拟议的项目如果成功，将把 DUSP26 确立为神经母细胞瘤的新治疗靶点，而针对 DUSP26 磷酸酶活性的小分子抑制剂可能为治疗神经母细胞瘤患者提供治疗益处。该提案的长期目标是通过识别和验证潜在的新型药物靶标来治疗这种破坏性儿童疾病，从而改善神经母细胞瘤患者的预后。 公共健康相关性：DUSP26 是双特异性磷酸酶家族的成员，在大多数 NB 细胞系和组织标本中特异性过表达，是体外神经母细胞瘤集落形成所必需的，并通过充当 p53 磷酸酶抑制 p53 肿瘤抑制功能，促进神经母细胞瘤对阿霉素诱导的细胞凋亡的抵抗。 神经母细胞瘤细胞。在本研究计划中，我们的目的是更好地了解 DUSP26 在神经母细胞瘤发展中的作用，并确定抑制 DUSP26 活性是否能够抑制神经母细胞瘤生长并增强原位小鼠模型中的神经母细胞瘤化疗敏感性。