Genomic approaches to identify SCLC biomarkers
Initial Award Abstract
Small cell lung cancer(SCLC) is the most deadly type of lung cancer and is associated with heavy cigarette smoking. Although the five-year survival rate is only 15%, the few patients detected with limited-stage disease have a much higher long-term survival. Therefore, it is crucial to identify targets and develop methods that could detect SCLC with high specificity in high-risk patients at early stages of cancer development.
We hypothesized that genes/markers that uniquely label SCLC in the lung would be good candidate for cancer detection. Our preliminary gene expression analysis comparing differences between SCLC lung tumors and normal lung tissue suggests that SCLC tumors have very distinct gene expression profiles with more than a thousand of genes changed their expression level for more than four fold. The defined timeline of tumor development in genetically engineered mouse models of SCLC enables us also to look into even early stage lesions, called hyperplasia. By cross comparison the gene expression patterns among normal lung cells, hyperplasia and SCLC tumors, we will gain a full understanding of early cancer development, but also identify a list of candidate markers for both hyperplasia and tumors. We will query other mouse model of SCLC as well as publicly available human SCLC gene expression dataset to filter our candidate marker list and finalize a list of markers that are generalizable and universal to most SCLC cases. We anticipate getting a list of 10 candidates for further characterization. We will then validate the candidates’ expression at protein level using immunohistochemistry on SCLC tumor sections from mouse and human. Given the imperative need for better therapies for SCLC, we will also test whether the candidate markers of SCLC have functional importance during tumor development. We will decrease the candidates’ expression by RNAi technology, and monitor the effect on tumor growth in mouse and also effects on proliferation and cell death.
An understanding of the markers that uniquely label SCLC in the lung may allow the clinical development of imaging methods that detect SCLC with high sensitivity and specificity. Functionally important candidates may also be potential drug targets for treating SCLC.