Castellanos Mario R, Pan Quintin
Division of Research, Department of Medicine, Staten Island University Hospital, Northwell Health, Staten Island, NY 10305, United States.
Department of Otolaryngology - Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States.
World J Otorhinolaryngol Head Neck Surg. 2016 Jul 19;2(2):68-75. doi: 10.1016/j.wjorl.2016.05.005. eCollection 2016 Jun.
Inactivation of the tumor suppressor p53 is the predominant pathogenetic event in head and neck squamous cell carcinoma (HNSCC). The p53 pathway in HNSCC can be compromised through multiple mechanisms including gene mutations, hyperactivation of endogenous negative p53 regulators and by the human papillomavirus E6 protein. Inactivation of p53 is associated with poor clinical response and outcome; therefore, restoration of the p53 signaling cascade may be an effective approach to ablate HNSCC cells. Viral approaches to restore p53 activity in HNSCC have been well-studied and shown modest activity in clinical trials. Recent work has focused on high-throughput screens and rational designs to identify and develop small molecules to rescue p53 function. Several p53-targeting small molecules have demonstrated very promising activity in pre-clinical studies but have yet progressed to the clinical setting. Further development of p53 therapies, in particular chemical approaches, should be prioritized and evaluated in the HNSCC setting.
肿瘤抑制因子p53的失活是头颈部鳞状细胞癌（HNSCC）主要的致病事件。HNSCC中的p53信号通路可通过多种机制受损，包括基因突变、内源性负性p53调节因子的过度激活以及人乳头瘤病毒E6蛋白的作用。p53失活与临床反应差和预后不良相关；因此，恢复p53信号级联反应可能是消融HNSCC细胞的有效方法。在HNSCC中恢复p53活性的病毒方法已得到充分研究，并在临床试验中显示出一定活性。最近的工作集中在高通量筛选和合理设计，以识别和开发能挽救p53功能的小分子。几种靶向p53的小分子在临床前研究中已显示出非常有前景的活性，但尚未进入临床阶段。应优先考虑并在HNSCC环境中评估p53疗法的进一步开发，特别是化学方法。
