肿瘤基因治疗的研究进展与思考

New Thoughts on Cancer Gene Therapy

肿瘤基因治疗的临床研究开展将近20年,迄今有近1000个项目已经或正在开展,涉及多种基因、多种载体以及绝大多数肿瘤类型、然而,基因药物在临床上对肿瘤的长效治疗效果尚无定论,出现这一现象的主要原因之一是对肿瘤发生与生长涉及多基因、多步骤的复杂病变过程缺乏系统认识。研究发现,肿瘤内众多的基因突变主要集中在几条已知的信号通路上,且突变的信号通路之间同时存在协同突变和拮抗突变两种作用。肿瘤内主要信号通路的协同突变不难理解,而拮抗突变也有相应的实验证据,如著名的EGFR和K-ras突变,在肺腺癌中各自的突变频率都非常高,但是很少有患者同时具有两个突变。"癌基因依赖"(Oncogene Addiction)理论也许能很好地解释信号通路突变的拮抗现象。这一理论认为,虽然肿瘤细胞的出现涉及到很多、复杂的遗传和表型的异常,但有些异常的出现明显依赖于某个肿瘤细胞增殖、存活相关的癌基因及其信号通路,如这一特定癌基因失活,这些相关的异常就会发生异于正常癌细胞的改变。无论是协同还是拮抗作用,都要求肿瘤治疗药物研发以癌变过程中发生异常的信号通路为标靶,而不是仅针对其中单个基因。因此,开发能同时调控多个信号通路的基因药物如micmRNA,或者多基因联合治疗将是肿瘤基因治疗可供选择的重要思路。

In the past two decades, approximately 1000 clinical cancer trials based on gene drugs have been reported on or were carried out. These trials used a variety of genes and vectors, and involved almost all kinds of tumor types. However, the sustaining curative effects of gene medicine needed further study. One important reason for this phenomenon was the lack of systemic knowledge about cancer itself. Carcinogenesis is a result of a multi-gene, multi-factor and multiple step process. Recent results have shown that the genetic alterations of a large number of genes functioned through a relatively small number of pathways and processes. Both concurrent and mutually exclusive mutations were found in cancer. The concurrent mutations were easy to understand, while the exclusive mutations were supported by the evidence of EGFR mutation and K-ras mutation. The mutant ratio of EGFR and K-ras was high in lung adenocarcinomas; however, few patients exhibited both mutations simultaneously. The theory of ＂Oncogene addiction＂ may provide a likely explanation for exclusive mutations. In its simplest form, oncogene addiction refers to the curious observation that a tumor cell, despite its plethora of genetic alterations, can seemingly exhibit dependence on a single oncogenic pathway or protein for its sustained proliferation and/or survival. Therefore, the best hope for therapeutic development may lie in the discovery of agents that target the physiologic effects of the altered pathways and processes rather than their individual gene components. So, targeting to the dysregulated genes with synergetic effects, such as microRNA or multi-gene therapy, may provide better success for cancer gene therapy.