Pancreatic cancer is the fourth leading cause of cancer deaths in the United States and has the worst survival rates of any cancer (The 1-year and 5-year survival rates are approximately 19% and 4%, respectively). This dismal picture of pancreatic cancer is mainly due to the lack of early diagnosis and effective surgical or chemotherapeutic treatments. In order to make real progress against this devastating disease, we are involved in research to discover basic genetic, molecular, and biochemical abnormalities and help translate the findings into practical and effective therapies for patients with pancreatic cancer. The development of targeted therapies based on distinguishing characteristics of pancreatic cancer cells versus normal cells relies on our ability to identify alterations that are present at high frequencies in pancreatic cancer cells.

In collaboration with an interdisciplinary team, we have utilized several genomic and biochemical approaches including whole genome expression profiling (DNA microarrays), gene copy number analysis (CGH microarrays), and tissue array immunohistochemistry to identify alterations in pancreatic cancer cells. We have identified and validated a list of upregulated and downregualted gene targets in pancreatic cancer cells and are currently developing new agents against some of these targets.

One gene we are studying is the mitotic serine/threonine kinase Aurora A (STK15). We have shown that the STK15 gene is amplified in pancreatic cancers and this amplification leads to overexpression of the STK15 protein. STK15 regulates the duplication of the microtubule organizing centers of the cells called centrosomes, and overexpression of STK15 causes increased centrosome numbers in cells. Increases in centrosome numbers can in turn lead to genomic instability which is thought to be one of the underlying factors driving the progression of many cancers. We have previously developed several small molecular inhibitors of the STK15 protein. Currently, we are using high throughput siRNA screening to identify sensitizers and biomarkers for Aurora kinase inhibitors.

Other drug targets being pursued in the lab include tumor suppressor genes such as DPC4 and p16 that are frequently inactivated in pancreatic cancer. We use synthetic lethal screening approaches to identify small molecules that selectively kill pancreatic cancer cells that harbor inactivating mutations in these tumor suppressor genes.

Dr. Han’s lab is also investigating the molecular mechanism of perineural invasion in pancreatic cancer. Perineural invasion is one of the most common features of pancreatic cancer and it causes pain. This pain has a tremendous impact on the patient quality of life. By understanding the mechanism of perineural invasion, we hope to identify molecular targets for the development of therapeutics that may alleviate the pain suffered by pancreatic cancer patients.