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.

肺癌是全球癌症死亡率的主要原因，因为它的出现较高和治愈率低。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CS的另一个病态结果，CS是由受感染的烟雾，颗粒和感染的病原体引起的炎症引起的，导致气道和肺泡的结构变化，导致气流减少。在50-80％的患有非小细胞肺癌（NSCLC）的患者中，COPD的年度肺癌的年发病率为0.8-1.7％。当前和前吸烟者患有COPD的人根据疾病的严重程度显示出3至10倍的肺癌风险。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策略，以减少公众对肺癌的燃烧。转录3（STAT3）的信号换能器和激活因子是调节细胞增殖，分化，凋亡和免疫响应的七个转录因子家族的成员之一。在NSCLC患者的肿瘤（包括KRAS突变肺腺癌（KM-LUAD））和几种NSCLC细胞系中，在COPD患者的肺中已证明了活化STAT3（PY-STAT3，TYR 705）的水平升高。激活STAT3的几种细胞因子，包括IL-6，IL-22和IL-17A，在注射过程中是在LUAD的小鼠模型中产生的，包括KM-LUAD和COPD类似COPD的小鼠模型。 TTI-101是STAT3（TVARDI THERAPEITACS）口服的可生物利用抑制剂，与具有高亲和力的STAT3的SH2结构域结合，并抑制蛋白质的二聚化和磷酸化。它不靶向其他酪氨酸激酶，口服后提供良好的血浆暴露，并且在大鼠和狗中进行28天的时间进行28天时，没有可检测的毒性。目前，正在对患有晚期癌症患者的I期临床试验进行评估（https://clinicaltrials.gov/show/nct03195699）。该任务顺序的目的是评估TTI-101在COPD相关LUAD模型鼠标中预防与COPD相关的NSCLC的功效。