Dm-dNK结合MCP-1对胃癌分子治疗的可行性研究

Metastasis is the main factor affecting the prognosis of patients with gastric cancer, a multi-stage, multi-step, multiple genes are involved in the process. Single-gene therapy for a cancer-causing genes are often difficult to work, however, take aside the many complex tumorigenic genes, to inhibit tumor cells with exogenous gene through some mechanism from pure destruction point of view is feasible. Tumor immunosuppressive microenvironment enriched is conducive to immune evasion, which is the major obstacle for in vivo gene therapy. Our previous study found that oncolytic adenovirus equipped Drosophila deoxynucleoside kinase (Dm-dNK) could selectively induce apoptosis of gastric cancer, and the nucleoside analogues could control the replication of adenovirus. It has been proved that the monocyte chemoattractant protein (MCP-1) can recruit and activate monocytes and promote the activity of M1 type macrophage, realease lysosomal, so that the tumor immune microenvironment can be destructed. This project intends to evaluate the killing effect of oncolytic adenovirus assembled Dm-dNK and MCP-1: Dm-dNK acts as suicide kinase to kill gastric cancer cells with oncolytic adenovirus, while a nucleoside analogue is used to ensure the safety of the virus. MCP-1 plays a immune activation factor to destroy tumor immune microenvironment, assisted destruction and inhibition of peritoneal metastasis. The project will confirm multiple anti-tumor properties of the MCP / Dm-dNK system and establish a new molecular treatment modality for the gastric cancer and metastasis.

胃癌转移是影响预后的主要因素，涉及多阶段、多基因参与的过程。针对某一致癌基因的治疗难以奏效，抛开众多复杂的致瘤基因，通过某种机制利用外源基因单纯杀伤肿瘤细胞却是切实可行的。而肿瘤免疫微环境的存在易使癌细胞免疫逃避，是体内基因治疗的主要障碍。我们前期研究发现溶瘤腺病毒搭载果蝇脱氧核苷激酶（Dm-dNK）能够靶向致胃癌细胞凋亡，并通过核苷类似物来控制腺病毒复制；并且已有研究证明单核细胞趋化蛋白（MCP-1）能够募集并活化单核细胞，促进M1型巨噬细胞的激活，破坏肿瘤免疫微环境。本项目拟评估溶瘤腺病毒装配Dm-dNK和MCP-1的新体系：Dm-dNK作为自杀激酶与溶瘤腺病毒对胃癌细胞联合杀伤，同时核苷类似物可以保证病毒的安全控制；MCP-1作为免疫激活因子破坏肿瘤免疫微环境，起到协同杀伤作用。本项目将证实MCP/Dm-dNK体系的多重抗肿瘤特性，旨在为治疗及阻遏胃癌转移建立一种新分子治疗模式。

已基本完成项目计划中的研究内容，建立了一套具有分子水平安全控制机制的选择复制型腺病毒介导的Dm-dNK自杀基因肿瘤杀伤体系，评估了溶瘤腺病毒装配Dm-dNK和MCP-1的新体系：ZD55-MCP-dNK，Dm-dNK作为自杀激酶与溶瘤腺病毒对胃癌细胞联合杀伤，同时核苷类似物可以保证病毒的安全控制；MCP-1作为免疫激活因子破坏肿瘤免疫微环境，起到协同杀伤作用。以体外和动物模型上的实验结果为依据，可能对肿瘤微转移病灶，为治疗及阻遏胃癌转移建立一种新分子治疗模式，为进一步注射针剂的开发及将来可能的临床应用打下基础。随着精准治疗理念的推广，新的治疗体系的建立已经并必将成为控制肿瘤疾病的关键措施，如果能成功用于临床，其社会及经济效益无法估量。课题在实施中发现采用MCP-1的表达框内目的基因的表达量较低，功能不显著，机制未明，因而导致文章撰写周期延长未能及时发表，多篇英文稿件审稿中。