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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。
Nearly 20 years of clinical research on cancer gene therapy have been carried out. Nearly 1,000 projects have been or are being conducted to date and involve a variety of genes, multiple carriers and the vast majority of tumor types. However, the long-term therapeutic effect of gene drugs on tumors The effect is not conclusive, one of the main reasons for this phenomenon is the lack of systematic understanding of the complex and pathological process involving multiple genes and multi-steps in tumorigenesis and growth. The study found that a large number of tumor gene mutations mainly concentrated in a few known signal pathways, and mutations in the signal pathways exist both synergistic mutations and antagonistic mutations in two roles. Co-mutations in the major signaling pathways in the tumor are not difficult to understand, and antagonistic mutations also have corresponding experimental evidence, such as the well-known EGFR and K-ras mutations in lung adenocarcinoma, each mutation frequency is very high, but few patients at the same time There are two mutations. “Oncogene Addiction ” theory may well explain the antagonism of signal pathway mutations. This theory suggests that while the appearance of tumor cells involves many, complex genetic and phenotypic abnormalities, some abnormalities appear to depend significantly on the oncogene and its signaling pathways associated with proliferation, survival of a tumor cell Inactivation of specific oncogenes, these related abnormalities will occur different from the normal changes in cancer cells. Whether synergistic or antagonistic, requires the development of oncology therapeutics to target abnormal signaling pathways in carcinogenesis, rather than targeting only a single gene. Therefore, the development of gene drugs that can simultaneously regulate multiple signal pathways, such as micmRNA, or multi-gene combination therapy will be an important idea for tumor gene therapy.