基于PLK1-Myc信号通路靶向治疗MYCN扩增神经母细胞瘤的机制研究

MYCN, encoding N-Myc, amplified in neuroblastoma predicts resistance to therapy and poor prognosis. MYCN amplified couples with N-Myc overexpression. Inhibition of MYCN expression/activity results in neuroblastoma regression in vitro and in vivo, indicated that therapeutic efforts aimed at N-Myc should have an important clinical relevance. However, pharmacological strategies that directly target N-Myc remain elusive. Our previous study has shown that inhibition of PLK1 induced potent apoptosis of MYCN-amplified neuroblastoma cells. However, the molecular mechanism and pharmacology of this PLK1 effection are largely unknown. Combining of approach of biochemistry, molecular biology and animal modeling, we aim to (1) explore the molecular mechanism of PLK1 regulating N-Myc; (2) illuminate the effection of PLK1 inhibitors killing MYCN-amplified neuroblastoma. This project will reveal the new mechanism of regulating N-Myc and provide proof-of-concept in administration of PLK1 inhibitor in MYCN-amplified neuroblastomas.

MYCN（编码N-Myc）在神经母细胞瘤中的扩增突变通常预示着耐药和预后不良。MYCN扩增导致N-Myc的过表达。体外和模式动物上已经证实，干预N-Myc的活性/表达可以有效抑制神经母细胞瘤的发生和发展，提示N-Myc可作为此类肿瘤的理想治疗靶点。然而，N-Myc的直接药物靶向目前仍难以实现，进一步寻找替代策略靶向N-Myc势在必行。申请人前期发现，PLK1抑制剂专一下调N-Myc并选择性诱发神经母细胞瘤细胞凋亡。然而其具体的分子机制及药理学作用尚未明了。据此，拟采用分子药理学、细胞生物学和模式动物等学科交叉的研究方法，深入(1) 研究PLK1调控N-Myc的分子机制；(2) 模式动物水平确证PLK1抑制剂对神经母细胞瘤的治疗效果。该项目的实施有望揭示N-Myc表达调控的新机制，为神经母细胞瘤的治疗提供潜在有效的靶向药物。

MYCN（编码N-Myc）在神经母细胞瘤中的扩增突变通常预示着耐药和预后不良。MYCN扩增导致N-Myc的过表达。体外和模式动物上已经证实，干预N-Myc的活性/表达可以有效抑制神经母细胞瘤的发生和发展，提示N-Myc可作为此类肿瘤的理想治疗靶点。然而，N-Myc的直接药物靶向目前仍难以实现，进一步寻找替代策略靶向N-Myc势在必行。申请人前期发现，PLK1抑制剂专一下调N-Myc并选择性诱发神经母细胞瘤细胞凋亡。然而其具体的分子机制及药理学作用尚未明了。据此，拟采用分子药理学、细胞生物学和模式动物等学科交叉的研究方法，深入(1)研究PLK1调控N-Myc的分子机制；(2)模式动物水平确证PLK1抑制剂对神经母细胞瘤的治疗效果。该项目的实施有望揭示N-Myc表达调控的新机制，为神经母细胞瘤的治疗提供潜在有效的靶向药物。