神经母细胞瘤（NB）是起源于神经嵴的小儿常见颅外恶性实体瘤。作为肿瘤抑制基因，P53突变是肿瘤细胞产生耐药导致治疗失败的重要原因之一。申请者发现，Akt抑制剂Perifosine可抑制NB肿瘤生长，而且P53突变肿瘤对其更敏感。前期对一P53突变NB细胞系microarray结果分析显示，P53信号通路是与Perifosine治疗最相关的通路。所以本项目将进一步在P53突变细胞系中证实该发现，并通过与P53野生型细胞的比较，研究Perifosine对突变型P53构象、对因突变而丧失的肿瘤抑制基因功能及对P53介导的凋亡通路的影响；同时，通过Perifosine与化疗药物联合使用，观察Perifosine治疗后NB的化疗敏感性的改变及与P53信号通路的关系。旨在探索Perifosine抑制肿瘤细胞生长新的作用机理，寻找解决P53突变引起的耐药新方法，为NB治疗提供新的、有效的理论指导。

Neuroblastoma (NB) is the most common extracranial solid tumor which derives from neural crest in children. As a tumor suppressor gene, P53 mutation is one of the main reasons for chemo-resistance and treatment failure in NB. Applicants found that Akt inhibitor Perifosine has anti-tumor growth effect, and NB cells/tumors with P53 mutation are more sensitive to it. A pioneering microarray study on a P53 mutated NB cell line treated with Perifosine indicates that P53 pathway is the most related pathway after Perifosine treatment. So, in this study we will further prove this finding in other P53 mutated NB cell lines, and by comparing to P53 wild type cells we will investigate the Perifosine effect on conformation changes to mutated P53, on tumor suppressor function lost by P53 mutation, and on the P53-mediated apoptosis pathway. We will also perform a combination study between Perifosine and chemotherapeutic drugs to study the changes of the chemo-sensitivity of NB cells/tumors in the presence of Perifosine, and the relationship between the changes and P53 signaling pathway. The goal of this study is to investigate the novel mechanism of perifosine effect on tumor growth inhibition and to look for new treatment for the P53 mutation-induced chemo-resistance. Our study will provide evidences for the improvement of treatment efficacy in NB, especially in those with P53 mutation and poor prognosis.