TARGETING STAT3 TO PREVENT NON-SMALL CELL LUNG CANCER (NSCLC) IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)

肺癌因其高发病率和低治愈率而成为全球癌症死亡的主要原因。吸烟（CS）导致炎症微环境失调，是肺癌的主要原因。慢性阻塞性肺疾病（COPD）是慢性阻塞性肺疾病的另一种病态后果，由吸入的烟雾、颗粒物和感染的病原体引起的炎症导致气道和肺泡的结构改变，导致气流减少。在被诊断为非小细胞肺癌（NSCLC）的患者中，有50-80%的患者先前存在COPD，而由COPD引起的肺癌年发病率为0.8-1.7%。根据疾病严重程度，目前和以前患有慢性阻塞性肺病的吸烟者患肺癌的风险增加3至10倍。因此，迫切需要在吸烟者和COPD患者等高危人群中采取早期预防肺癌的策略，以减轻肺癌的公共负担。STAT3是调控细胞增殖、分化、凋亡和免疫应答的转录因子家族的7个成员之一。在COPD患者的肺部、非小细胞肺癌患者的肿瘤（包括KRas突变型肺腺癌（KM-LUAD））和几种非小细胞肺癌细胞系中，已证实激活的STAT3 （pY-STAT3, Tyr 705）水平升高。几种激活STAT3的细胞因子，包括IL-6、IL-22和IL-17A，在LUAD小鼠模型（包括KM-LUAD和copd样小鼠模型）的炎症过程中产生。TTI-101是一种口服生物可用的STAT3抑制剂（Tvardi Therapeutics），可以高亲和力地结合STAT3的SH2结构域，抑制STAT3蛋白的二聚化和磷酸化。它不针对其他酪氨酸激酶，在口服给药后提供良好的血浆暴露，并且在大鼠和狗中使用28天没有产生可检测到的毒性。它目前正在晚期癌症患者的I期临床试验中进行评估（https://clinicaltrials.gov/show/NCT03195699）。本课题旨在评价TTI-101在COPD相关LUAD模型小鼠中预防非小细胞肺癌合并COPD的疗效。

Lung cancer is the leading cause of cancer mortality worldwide due to its high incidence and low cure rate. Cigarette smoking (CS), which causes a dysregulated inflammatory microenvironment, is the principal cause of lung cancer. Chronic Obstructive Pulmonary Disease (COPD) is another morbid consequence of CS that results from inflammation induced by inhaled smoke, particulates and infecting pathogens that leads to structural changes in airways and alveoli, resulting in reduced airflow. Between 50-80% of patients diagnosed with Non-Small Cell Lung Cancer (NSCLC) have preexisting COPD and the annual incidence of lung cancer arising from COPD is 0.8-1.7%. Current and former smokers with COPD display a 3- to 10-fold increased risk of lung cancer based on their disease severity. Therefore, strategies to prevent lung cancer in its earliest stages among high-risk individuals such as smokers and COPD patients are urgently needed to reduce the public burden of lung cancer. 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. Increased levels of activated STAT3 (pY-STAT3, Tyr 705) have been demonstrated in lungs of COPD patients, in tumors of NSCLC patients, including KRas mutant lung adenocarcinoma (KM-LUAD), and several NSCLC cell lines. Several cytokines that activate STAT3, including IL-6, IL-22 and IL-17A are shown to be generated during inflammation in mouse models of LUAD, including KM-LUAD and a COPD-like mouse model. TTI-101, an orally bioavailable inhibitor of STAT3 (Tvardi Therapeutics), binds to the SH2 domain of STAT3 with high affinity and inhibits the protein’s dimerization and phosphorylation. It does not target other tyrosine kinases, provides good plasma exposure following oral administration, and produces no detectable toxicity when administered for a period of 28 days in rats and dogs. It is currently being evaluated in a Phase I clinical trial in patients with advanced cancers (https://clinicaltrials.gov/show/NCT03195699). The purpose of this Task Order is to evaluate the efficacy of TTI-101 for the prevention of NSCLC associated with COPD in a mouse of model of COPD-associated LUAD.