DUSP26: A Novel Therapeutic Target in Neuroblastoma

描述（由申请人提供）：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，迫切需要新的治疗方法。本提案将通过界定以下方面的作用来实现这一目标。在我们的初步研究中，我们发现DUSP 26在大多数NB细胞系和组织标本中特异性过表达。DUSP 26是体外神经母细胞瘤集落形成所需的，并通过作为p53磷酸酶抑制神经母细胞瘤细胞中的p53肿瘤抑制功能来促进神经母细胞瘤对阿霉素诱导的细胞凋亡的抗性。因此，DUSP 26作为p53特异性磷酸酶抑制p53功能，以响应p53野生型神经母细胞瘤中的遗传毒性应激。大多数神经母细胞瘤保持功能性p53和凋亡机制，这些机制在大多数原发和复发病例中受到抑制。因此，通过抑制DUSP 26磷酸酶活性来重新激活p53活性代表了针对这种癌症的有吸引力的治疗方法。 这项工作的中心假设是DUSP 26是调节神经母细胞瘤生长、转移和化疗耐药性的重要因子。所提出的实验将通过分析DUSP 26在神经母细胞瘤发育中的生物学作用来测试该假设，并确定DUSP 26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DUSP 26敲低是否改变原位小鼠模型中的神经母细胞瘤肿瘤生长; 2）确定DUSP 26敲低是否改变原位小鼠模型中的神经母细胞瘤肿瘤化学抗性; 3）确定新的DUSP 26抑制剂是否改变原位小鼠模型中的神经母细胞瘤肿瘤生长;（4）探讨DUSP 26在神经母细胞瘤中的作用机制。 如果成功，拟议的项目将确立DUSP 26作为神经母细胞瘤的新治疗靶点，针对DUSP 26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点来改善神经母细胞瘤患者的预后，用于治疗儿童这种毁灭性疾病。

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.