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。特别是前吸烟者，由于其气道中存在持续的遗传异常以及由先前烟草暴露引起的COPD/肺气肿引起的慢性炎症，其肺癌风险升高。化学预防是减少这一高危人群未来癌症的一个明显途径，但目前缺乏安全有效的药物。 信号转导子和转录激活子3（STAT 3）是调节细胞增殖、分化、凋亡和免疫应答的转录因子家族的七个成员之一。尽管STAT 3的激活在正常细胞中是短暂的和高度调节的，但它在包括肺癌在内的几种类型的癌症中是组成型活性的。最近的研究结果表明，用环状STAT 3诱饵（CS 3D）靶向活化的STAT 3可能是非小细胞肺癌以及其他烟草相关癌症的成功预防性干预。 由Jennifer Grandis博士及其同事开发的CS 3D是一种环化双链寡核苷酸，含有15个碱基对序列，对应于STAT 3靶基因的STAT 3反应元件。CS 3D与STAT 3二聚体相互作用，作为分子库竞争性抑制二聚体与STAT 3靶基因启动子的结合并诱导p-STAT 3蛋白酶体降解。CS 3D无毒、热稳定，在全身给药后仍保持活性。本任务指令旨在评价CS 3D对暴露于烟草致癌物4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（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).