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

针对 STAT3 预防慢性阻塞性肺疾病 (COPD) 患者的非小细胞肺癌 (NSCLC)

• 批准号: 10705395
• 负责人: POWELL BROWN
• 金额: $ 109.8万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-03-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705395
• 关键词: Advanced Malignant Neoplasm; Affinity; Air Movements; Alveolus; Apoptosis; Binding; Cancer Etiology; Cancer Patient; Cancer cell line; Canis familiaris; Cell Proliferation; Chronic Obstructive Pulmonary Disease; Development; Diagnosis; Dimerization; Dose; Family; Immune response; Incidence; Individual; Inflammation; Inflammatory; Interleukin-17; Interleukin-6; Lung; Lung Adenocarcinoma; Malignant neoplasm of lung; Non-Small-Cell Lung Carcinoma; Oral; Oral Administration; Particulate; Patients; Phase I Clinical Trials; Phosphorylation; Plasma; Prevention; Preventive; Protein Tyrosine Kinase; Rattus; Risk; Safety; Severity of illness; Smoker; Stat3 protein; Therapeutic; Toxic effect; base; candidate marker; cigarette smoking; cytokine; design; efficacy evaluation; former smoker; high risk; inhibitor; interleukin-22; member; mortality; mouse model; mutant; pathogen; prevent; smoke inhalation; src Homology Region 2 Domain; transcription factor; tumor

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.

肺癌发病率高，治愈率低，是世界范围内癌症死亡的主要原因。吸烟导致炎症微环境失调，是导致肺癌的主要原因。慢性阻塞性肺疾病(COPD)是CS的另一种病态后果，由吸入烟雾、颗粒物和感染病原体引起的炎症导致呼吸道和肺泡的结构改变，从而导致气流减少。在被诊断为非小细胞肺癌(NSCLC)的患者中，50-80%的患者已有COPD，每年由COPD引起的肺癌发病率为0.8-1.7%。根据疾病的严重程度，现在和以前患有COPD的吸烟者患肺癌的风险增加了3到10倍。因此，迫切需要在吸烟者和COPD患者等高危人群中预防肺癌的早期阶段的策略，以减轻肺癌的公共负担。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。在COPD患者的肺、NSCLC患者的肿瘤中，包括KRAS突变肺腺癌(KM-LUAD)和几个NSCLC细胞系中，已发现激活的STAT3(Py-STAT3，Tyr705)水平升高。包括KM-LUAD和COPD样小鼠模型在内的LUAD小鼠模型在炎症过程中产生了几种激活STAT3的细胞因子，包括IL-6、IL-22和IL-17A。TTI-101是一种口服生物可用的STAT3抑制剂(Tvardi Treeutics)，它与STAT3的SH2结构域高亲和力结合，并抑制该蛋白的二聚化和磷酸化。它不针对其他酪氨酸激酶，在口服后提供良好的血浆暴露，在大鼠和狗身上给药28天时不会产生可检测到的毒性。目前正在对晚期癌症患者进行I期临床试验(https://clinicaltrials.gov/show/NCT03195699).进行评估本任务单旨在评价TTI-101对COPD相关LUAD小鼠模型中非小细胞肺癌的预防作用。