靶向黄嘌呤氧化酶的抗肺腺癌研究

Aberrant metabolism in tumor cells is one of the ten hallmarks of tumor and plays important role in tumorigenesis. Nucleotide is one of the important substances to support the rapid proliferation of tumor cells, while the role of nucleotide catabolism in tumor remains largely unknown. Xanthine oxidase is the rate-limiting enzyme in the purine catabolism. Our preliminary study found that Xanthine oxidase overexpressed in lung cancer tissues and its expression predicted poor prognosis in lung adenocarcinoma patients. In this study, the role of xanthine oxidase in the growth and survival of lung adenocarcinoma cells under normal cultural or stressed conditions, i.e. hypoxia, starvation, will be studied and the insight mechanism will be elucidated. The modulators of Xanthine oxidase obtained in the preliminary study will be further modified to discover new agents with improved anticancer activity. We will further study the therapeutic strategy based on modulators of xanthine oxidase for the therapy of lung adenocarcinoma. This study will not only reveal the role of xanthine oxidase in lung adenocarcinoma and validate it as a potential therapeutic target for lung cancer, but also lead to discover of modulators of xanthine oxidase with brand-new mode of action, which will provide new strategy for the therapy of lung adenocarcinoma, especially those harboring mutation in EGFR or KRAS, which are resistant to available therapeutics.

肿瘤代谢异常是肿瘤的十大特征之一，在肿瘤的发生发展中发挥举足轻重的作用。核苷酸是肿瘤细胞快速增殖重要的物质基础，其分解代谢在肿瘤发生发展的作用研究非常有限。黄嘌呤氧化酶是嘌呤分解代谢过程中的重要限速酶。申请人前期研究发现黄嘌呤氧化酶在肺癌组织显著高表达，而且其表达水平与病人预后显著负相关，下调黄嘌呤氧化酶能够抑制肺癌细胞增殖和存活。本课题拟研究黄嘌呤氧化酶对肺腺癌细胞特别是在应激情况如缺氧、饥饿下增殖、存活中的作用及其机制；并对前期得到的黄嘌呤氧化酶活性调节剂进行进一步结构修饰改造，发现活性更高的化合物，并研究其抗肿瘤作用和机制；进一步开展基于黄嘌呤氧化酶活性调节剂肺腺癌治疗策略的研究。本课题不仅将阐明黄嘌呤在肺腺癌发生发展中的作用和确证其作为肺癌治疗靶标的潜力，同时发现全新作用模式的黄嘌呤活性调节剂，极有可能为肺腺癌特别是对现有治疗耐受的EGFR和KRAS突变肺腺癌发现新的治疗契机。

黄嘌呤氧化还原酶（xanthine oxidoreductase, XOR）是嘌呤分解代谢途径中的限速酶，催化次黄嘌呤氧化为黄嘌呤以及进一步将黄嘌呤氧化为尿酸。XOR表达和活性在多种肿瘤中异常，且与肿瘤患者预后相关。研究表明XOR在肺癌病人的肿瘤组织中显著高表达。然而，其在肺癌的具体作用机制尚不清楚。因此深入研究XOR 在肺癌中发挥的作用和探明分子机制对于发现新作用模式的肺癌治疗药物具有重要意义。研究发现XOR在肺腺癌组织以及肺腺癌细胞系中高表达，并且XOR表达上调与肺腺癌病人不良预后显著相关，敲除XOR或抑制XOR活性能够通过阻碍未折叠蛋白反应和自噬产生核糖、氨基酸等代谢物质抑制饥饿肺腺癌细胞存活，补充嘌呤核苷以及氨基酸能够挽救细胞存活；发现新化合物545能够结合黄嘌呤氧化酶并剂量依赖性地竞争性激活黄嘌呤氧化酶，诱导肺腺癌细胞产生活性氧，抑制多种肺腺癌细胞增殖，其活性与SOD1表达负相关；发现抑制XOR能够增强诱导UPR及自噬的抗肿瘤药物2-DG对肺腺癌的体内外抗肿瘤活性。以上研究为揭示XOR在肺腺癌发生发展中的作用提供了新的线索，为XOR激活剂的发现提供了先导化合物，为靶向代谢治疗肺腺癌提供的新的策略。.通过本项目的实施，发表SCI研究论文8篇，1名研究骨干晋升为副研究员，培养博士研究生毕业3名，博士后出站1名。