Ninety million former and current smokers in the United States (U.S.) are at elevated risk for lung cancer, the leading cause of cancer deaths in Texas, the U.S. and worldwide. Small-cell lung cancer (SCLC) occurs almost exclusively in smokers, and is particularly deadly with a mere 7% overall survival rate. This dismal outcome is attributed to late-stage diagnosis, and has exhibited little progress in treatment in the past decades. Knowledge of critical molecular events early in SCLC development is lacking. Such events may serve as biomarkers to aid in earlier detection, inform our understanding of how SCLC initiates and progresses, and comprise targets for personalized treatment. We and ot...

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Ninety million former and current smokers in the United States (U.S.) are at elevated risk for lung cancer, the leading cause of cancer deaths in Texas, the U.S. and worldwide. Small-cell lung cancer (SCLC) occurs almost exclusively in smokers, and is particularly deadly with a mere 7% overall survival rate. This dismal outcome is attributed to late-stage diagnosis, and has exhibited little progress in treatment in the past decades. Knowledge of critical molecular events early in SCLC development is lacking. Such events may serve as biomarkers to aid in earlier detection, inform our understanding of how SCLC initiates and progresses, and comprise targets for personalized treatment. We and others have previously found that airways of smokers which appeared "normal" under a microscope in fact bore molecular changes that resembled those of tumors, identifying these tissues as at-risk for malignancy and serving as accessible biomarkers. Our studies were conducted for non-small cell lung cancer, whereas such investigations of airway changes in SCLC have not been conducted.

In this proposal, we propose to study airways and primary tumors of SCLC patients as well as such tissues from individuals who appear at high-risk for lung cancer but exhibit benign nodules only. Our goal is to identify unique molecular characteristics in the airways of SCLC patients, by comparing these groups at bulk and single-cell levels. We will identify DNA mutations and gene expression changes in the airway samples via "bronchial brushing" during diagnosis or screening. Contrasting profiles in patients with SCLC to those with benign nodules will allow us to identify alterations in the genome that promote SCLC initiation and progression. These discoveries will enhance our understanding of the earliest development of SCLC, and suggest biomarkers for early detection and targets for novel clinical strategies in prevention and treatment of this highly aggressive and deadly disease.

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