Identifying new markers for diagnosis and treatment of SCLC

Lung cancer is the second most common cancer in the United States but has the highest mortality rate, creating an enormous socioeconomic burden. About 15% of all lung cancer cases are small cell lung cancer (SCLC), an extremely aggressive form of lung cancer. Almost all cases of SCLC are caused by cigarette smoking. Despite the investment of an enormous amount of effort and resources in the past few decades, the treatment options are still very limited. The standard treatment remains chemotherapy and radiotherapy. Neither has the survival rate of SCLC significantly improved. Two-year survival rate for advanced SCLC is only 5%. These low numbers are even more depressing when compared with the drastically improved five-year survival rates enjoyed by many other types of solid tumors such as breast cancer and prostate cancer. These achievements are due to early diagnosis and effective treatment. This highlights the urgent need for basic research to obtain markers for early SCLC diagnosis and candidates for targeted therapies. Targeted therapies employ drugs that target a selective pathway required for cancer cell survival and promise to be the cornerstone of future cancer treatment. Studies of human SCLC are severely restricted by the lack of human tumor tissues. This originates from the fact that standard treatment for SCLC patients does not involve surgery since it is assumed that distant metastasis has occurred by the time of diagnosis. Surgery has not been shown to improve the survival rate. On rare occasions when SCLC patients were operated on, tumor tissues can be used for cell line derivation and studies to uncover the molecular mechanisms of tumor development. To overcome these difficulties in SCLC studies, in this application, we developed a mouse model of human SCLC based on mutations frequently found in human SCLC. We showed that this mouse model of SCLC exhibits essential features of human SCLC. This addressed one of the most severe criticisms of using mice to model human SCLC. We also provided experimental evidence to support the notion that SCLC came from pulmonary neuroendocrine cells (PNECs), a rare cell population in the lung. In this application, we propose to isolate cancerous PNECs for whole-genome analysis. We will perform RNA-Seq, a technique that allows us to obtain information about the RNA contents of transformed PNECs. We will also conduct Exome sequencing, a method to obtain sequences of every gene in the human genome. This would allow us to capture mutations in the cancer genome at a global scale. Both studies will provide candidates as markers of early SCLC diagnosis and candidates for targeted therapies. Successful execution of this application will achieve two major goals. The first goal is to identify markers for early SCLC diagnosis. This is not feasible using human SCLC cell lines and tumors since they are derived from tissues of end-stage diseases. The second goal is to employ a more systematic approach to identify candidates for targeted therapies. While targeted therapies have been applied to SCLC patients, none has made their way into daily practice. This highlights the importance of a genomic approach to search for new candidates. This method would also pave the way for personalized medicine in which distinct sets of drugs are used to treat individual cancer patients.