aDepartment of Medical Oncology, Dana-Farber Cancer Institute, and Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA bDepartment of Immunology, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, Brazil.
Curr Opin Oncol. 2013 Nov;25(6):652-8. doi: 10.1097/01.cco.0000432528.88101.1a.
A lack of effective treatments for advanced cancer remains a major challenge in oncology. Because cancer is a disease associated with aberrant gene expression patterns, transcription factors, which serve as the convergence points of oncogenic signaling and are functionally altered in many cancers, hold great therapeutic promise.
Many human cancers are dependent on the inappropriate activity of oncogenic transcription factors. By contrast, normal cells can often tolerate disruption of these proteins with little toxicity. Direct inhibition of transcription factor expression (e.g., with RNA interference or microRNAs) and DNA binding (e.g., with oligodeoxynucleotide decoys or pyrrole-imidazole polyamides) has demonstrated antitumor responses with minimal side-effects. New strategies of targeting transcription factors include disrupting critical protein-protein interactions, and restricting binding at the epigenetic level by modulating chromatin accessibility. Moreover, targeting transcription factors in tumor-associated immune cells has the potential to overcome tumor immunoresistance.
Transcription factors are an important target for cancer therapy, both through direct anticancer effects and immunomodulatory actions. Newly developed delivery systems that specifically target tumor cells also create opportunities for successes in targeting transcription in cancer.
癌症治疗的一大挑战是缺乏有效治疗方法。因为癌症是一种与异常基因表达模式相关的疾病，转录因子作为致癌信号的汇聚点，在许多癌症中功能发生改变，因此具有很大的治疗潜力。
许多人类癌症依赖于致癌转录因子的异常活性。相比之下，正常细胞通常可以耐受这些蛋白的破坏，而毒性很小。直接抑制转录因子的表达（例如，使用 RNA 干扰或 microRNAs）和 DNA 结合（例如，使用寡脱氧核苷酸诱饵或吡咯-咪唑聚酰胺）已显示出抗肿瘤反应，副作用最小。靶向转录因子的新策略包括破坏关键的蛋白-蛋白相互作用，并通过调节染色质可及性在表观遗传水平上限制结合。此外，靶向肿瘤相关免疫细胞中的转录因子有可能克服肿瘤免疫抵抗。
转录因子是癌症治疗的一个重要靶点，既可以通过直接的抗癌作用，也可以通过免疫调节作用。专门针对肿瘤细胞的新开发的递药系统也为靶向癌症转录提供了成功的机会。
