DUSP26: A Novel Therapeutic Target in Neuroblastoma

描述(申请人提供)：神经母细胞瘤是最常见的儿童颅外恶性实体瘤，耐药是导致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。这项提案将通过定义的作用来实现这一目标。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地过表达。DUSP26是神经母细胞瘤体外集落形成所必需的，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，促进神经母细胞瘤对阿霉素诱导的细胞凋亡的抵抗。因此，在P53野生型神经母细胞瘤中，DUSP26作为一种P53特异性磷酸酶来抑制P53的功能，以响应遗传毒性应激。大多数神经母细胞瘤维持着功能性的P53和凋亡机制，而这些机制在大多数原发和复发病例中被抑制。因此，通过抑制DUSP26磷酸酶活性来重新激活P53活性代表了一种有吸引力的治疗方法。这项工作的中心假设是DUSP26是调节神经母细胞瘤生长、转移和化疗耐药的关键因子。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验证这一假设，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的生长并增强神经母细胞瘤的化疗敏感性。本应用的具体目的是：1)确定DUSP26基因敲除是否改变原位小鼠模型中神经母细胞瘤的生长；2)DUSP26基因敲除是否改变原位小鼠模型中神经母细胞瘤的化疗耐药性；3)确定新型DUSP26抑制剂是否改变原位小鼠模型中神经母细胞瘤的生长；以及4)确定DUSP26在神经母细胞瘤中对阿霉素治疗的作用机制。如果该项目成功，将使DUSP26成为神经母细胞瘤的新的治疗靶点，而针对DUSP26磷酸酶活性的小分子抑制剂可能为神经母细胞瘤患者的治疗提供益处。这项建议的长期目标是通过确定和验证潜在的可用药靶点来改善神经母细胞瘤患者的预后，以治疗儿童这种毁灭性的疾病。

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.