TASK ORDER: PREVENTING LUNG CANCER BY TARGETING ACTIVATED STAT3

任务顺序：通过针对激活的 STAT3 来预防肺癌

• 批准号: 10269147
• 负责人: MARGIE CLAPPER
• 金额: $ 77.99万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2023-03-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10269147
• 关键词: Apoptosis; Base Pairing; Binding; Biological Markers; Butanones; Cause of Death; Cell Proliferation; Chemoprevention; Chronic; Chronic Obstructive Airway Disease; Family; Future; Genes; Immune response; Inflammation; Inhalation; Malignant Neoplasms; Malignant neoplasm of lung; Methods; Molecular; Molecular Abnormality; Mus; Non-Small-Cell Lung Carcinoma; Normal Cell; Oligonucleotides; Periodicity; Preventive; Preventive Intervention; Pulmonary Emphysema; Research; Response Elements; Risk; STAT3 gene; Smoker; Stat3 protein; Tobacco-Associated Carcinogen; Tobacco-Related Carcinoma; Travel; United States; cancer risk; cancer type; dimer; dosage; lung cancer prevention; member; prevent; promoter; tobacco exposure; transcription factor

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).

肺癌仍然是美国癌症死亡的第一大原因。戒烟者的肺癌风险尤其升高，因为他们的气道中存在持续的基因异常，以及之前接触烟草引起的慢性阻塞性肺病/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) 是调节细胞增殖、分化、凋亡和免疫反应的转录因子家族的七个成员之一。尽管 STAT3 的激活在正常细胞中是短暂的且受到高度调控，但它在包括肺癌在内的多种癌症中具有持续活性。最近的研究结果表明，用环状 STAT3 诱饵 (CS3D) 靶向激活的 STAT3 可能是对非小细胞肺癌以及其他烟草相关癌症的成功预防干预措施。 CS3D 由 Jennifer Grandis 博士及其同事开发，是一种环化双链寡核苷酸，包含与 STAT3 靶基因的 STAT3 响应元件相对应的 15 个碱基对序列。 CS3D 与 STAT3 二聚体相互作用，充当分子库，竞争性抑制二聚体与 STAT3 靶基因启动子的结合，并诱导 p-STAT3 蛋白酶体降解。 CS3D无毒、热稳定，全身给药后仍保持活性。该任务令的目的是评估 CS3D 对暴露于烟草致癌物 4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮 (NNK) 的小鼠预防肺癌的作用。