TASK ORDER: PREVENTING LUNG CANCER BY TARGETING ACTIVATED STAT3

肺癌仍然是美国癌症死亡的头号原因。前吸烟者患肺癌的风险尤其高，这是因为他们的呼吸道存在持续性的遗传异常，以及以前接触烟草导致的慢性阻塞性肺病/肺气肿引起的慢性炎症。对于这一高危人群来说，化学预防是减少未来癌症的明显途径，但目前缺乏安全有效的药物。 信号转导和转录激活因子3(STAT3)是调控细胞增殖、分化、凋亡和免疫反应的转录因子家族的7个成员之一。尽管STAT3的激活在正常细胞中是短暂的，并且受到高度调控，但它在包括肺癌在内的几种类型的癌症中都是结构性活跃的。最近的研究结果表明，靶向激活的STAT3与环状STAT3诱饵(CS3D)可能是一种成功的预防干预非小细胞肺癌以及其他烟草相关的癌症。 CS3D由詹妮弗·格兰迪斯博士及其同事开发，是一种环状双链寡核苷酸，包含与STAT3靶基因的STAT3反应元件相对应的15个碱基对序列。CS3D与STAT3二聚体相互作用，竞争性地抑制二聚体与STAT3靶基因启动子的结合，诱导p-STAT3蛋白酶体降解。CS3D无毒，热稳定，全身给药后仍保持活性。本任务单的目的是评估CS3D对暴露于烟草致癌物4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK)的小鼠肺癌的预防作用。

Lung cancer remains the number one cause of death from cancer in the United States. Ex-smokers in particular have an elevated lung cancer risk due to the presence of persistent genetic abnormalities in their airways and chronic inflammation from COPD/emphysema induced by previous tobacco exposure. Chemoprevention is an obvious avenue for reducing future cancer for this at-risk group, but safe and efficacious agents are currently lacking. Signal transducer and activator of transcription 3 (STAT3) is one of the seven members of a family of transcription factors that regulates cell proliferation, differentiation, apoptosis, and the immune response. Although the activation of STAT3 is transient and highly regulated in normal cells, it is constitutively active in several types of cancer, including lung cancer. Recent findings suggest that targeting activated STAT3 with a cyclic STAT3 decoy (CS3D) could be a successful preventive intervention in non-small cell lung cancer as well as other tobacco-related cancers. CS3D, developed by Dr. Jennifer Grandis and colleagues, is a circularized double-stranded oligonucleotide containing a 15 base-pair sequence corresponding to the STAT3 response element of the STAT3 target genes. CS3D interacts with STAT3 dimers, acting as a molecular sink to competitively inhibit binding of the dimer to the promoters of STAT3 target genes and inducing p-STAT3 proteasomal degradation. CS3D is non-toxic, thermally stable, and remains active after systemic administration. The purpose of this Task Order is to evaluate CS3D for the prevention of lung cancer in mice exposed to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).