Aiolos小分子抑制剂沙利度胺对肺癌转移的影响

Lung cancer is one of the cancers with the highest morbidity and mortality. The clinical behavior and prognosis of lung cancer is very poor. No effective target therapy was used clinically for lung cancer,especially small cell lung cancer. Comparing with traditional chemotherapeutic drugs, small molecular targeting agents have presented more significant efficacy and less side effects on patients due to their definite substrates, which are suitable for the personalized therapy applications. Our preliminary data showed the hematopoietic-specific transcription factor Aiolos is ectopically expressed in lung cancer cells, which plays a critical role in weakening the anoikis sensitivity of cancer cells by suppressing P66shc, raises the probability of tumor long range metastasis. Based on the specific capacity of degradation Ikaros and Aiolos, Thalidomide has been extensively utilized for the treatment of Multiple myeloma. Here, the objective of this proposal is focused on testing the suppression capacity of Thalidomide on lung cancer metastasis through down-regulation Aiolos, in order for reducing lung cancer mortality. We propose to use the spontaneous SCLC mice model and Patient-derived xenograft (PDX) model to mimic patient’s internal environment to testify the anti-lung cancer activity of Thalidomide, in order to obtain a new and effective strategy for improving thetherapeutic efficacy of small cell lung cancer.

肺癌是世界上发病率和死亡率最高的恶性肿瘤之一，肺癌尤其是小细胞肺癌，缺少有效的靶向治疗手段。相对于传统化疗药物而言，小分子靶向药物的临床应用可以使患者获得针对性更强的治疗，由于其具有作用位点明确，副作用小的特点，对于患者意义更大。前期工作中发现血细胞特异性转录因子Aiolos（属于锌指蛋白Ikaros家族）在肺癌当中存在异位表达，其功能主要在于通过抑制P66shc蛋白的表达降低肿瘤细胞对失巢凋亡的敏感性，促进肿瘤细胞的远端转移。基于针对Ikaros与Aiolos蛋白的抑制能力，沙利度胺已经应用于多发性骨髓瘤的治疗。我们的研究以肺癌中异位表达的Aiolos作为药物作用靶点，尝试使用沙利度胺特异性地抑制肺癌细胞由于Aiolos异位表达而增强的转移能力，降低肺癌致死率。我们研究的重点在于使用小鼠小细胞肺癌自发肿瘤模型和PDX模型验证沙利度胺的抗肿瘤特性，以获得小细胞肺癌有效的靶向治疗药物。