Translational Research in Lung and Pancreatic Cancer
Lung and pancreatic cancers are the two most deadly cancers with overall five-year survival rates of 15% and 2-5%. Understanding the molecular basis of their malignancy will provide insights for improving the early diagnosis and treatment of against these diseases.
Our primary goal in lung cancer research is to identify genes or proteins that are predictive of poor prognosis in lung cancer patients who have had their tumors resected by surgery.
In the laboratory, we use lung cancer cell lines as in vitro models, snap-frozen and paraffin embedded human lung cancer tissues as primary tumor model, orthotopic implantation of lung cancer cells in immune deficient mice as in vivo model, and the recent development of organoids from primary and PDX tissue to understand the biology of lung cancer cells and evaluate the biomarker potential identified through computational and functional analysis. Clinical tissue samples are used to identify tumor-associated mutations, gene expression changes and gene copy number aberrations that correlate with poor clinical outcome. Additional studies are performed on cell lines with different metastatic potential.
Candidate prognostic genes are identified using high throughput and genome wide microarray techniques. Validation of their prognostic significance in large cohorts of cancer samples is performed using high throughput realtime RT-PCR and tissue microarray techniques.
The mechanisms that these genetic aberrations may affect the biology of lung cancer cells are then studied using in vitro cell line models and in vivo orthotopic metastatic lung cancer model.
Prognostic genes are potential target for the development of new anti-cancer drugs. Special interests and emphasis are on ras oncogene, Met tyrosine kinase receptor, epidermal Growth factor receptor (EGFR) and Phosphatidyl-inositol-3 kinase (PI3K).
Additional studies focus on discovering biomarkers that can predict response to newly developed targeted anticancer drugs, such as inhibitors of EGFR, PI3K, MET, ALK and Nrf2-Keap1. Our lab has adopted the (1x1x1) PDX drug screening from Gao et al. Nature med 2015 to identify models responding to these targeted inhibitors. We then correlate the drug sensitivity to the molecular profiles of these PDXs to identify biomarkers of drug response.
The laboratory is also actively studying the molecular basis of multi-stage development of human pancreatic cancer. A majority of pancreatic cancers arise from duct epithelium, and the latter may also differentiate into islet cells. This suggests the potential 'stem-cell' nature of pancreatic duct cells.
My laboratory was the first one to establish primary cultures of normal duct cells from adult human pancreas, and immortalized cell lines derived from these normal duct cells. Clones of immortal cell lines were isolated and they showed near normal genotype and phenotype. These cells are being used as in vitro models to study the role of oncogenes and tumor suppressor genes in the malignant transformation of pancreatic duct cells.
The goal of this project is to delineate the biological and molecular mechanisms that are critical for transforming normal pancreatic duct cells into pancreatic cancer cells. Knowledge derived from this study will be used to develop markers for early detection of pancreatic cancer, as well as provide insights on developing novel strategies to prevent and treat pancreatic cancer.
