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

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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.