Dr. Nagathihalli has developed a highly productive research program in pancreatic carcinogenesis. The scientific questions he wishes to answer are critical, unresolved issues in the field. To overcome Kras un-druggability and to increase the survival rate of pancreatic cancer patients, his innovative solution is to target the aberrant cyclic AMP response element-binding protein (CREB), a downstream effector of RAS signaling. He plans to expand his CREB oncogene-focused project through collaborations with lung, breast, gastric and esophageal cancer researchers at Sylvester Cancer Center, emphasizing therapeutic targeting. CREB, a transcription factor critical for pancreatitis and pancreatic cancer progression, and is hyper activated in smokers and alcoholics. Dr. Nagathihalli group developed CREB knockout model, used genetic mouse models and human patient tissues to look at normal pancreas cells, a type of pre-cancerous pancreas lesion called PanIN, and pancreatic cancer cells. In the normal cells, CREB express less but once cells become malignant, CREB contributes to the cancer's growth. This activity has made it an attractive target for developing potential pancreatic cancer treatments.

Dr. Nagathihalli group is testing CREB inhibitors for prevention of the cancer induction. Because all cancers are very distinct from one another and behave very differently to various therapies, it is critically important to identify specific genetic markers within a tumor that may predict the best response to a particular treatment amongst different patients. In this way, we can begin to personalize treatments based on a signature we know will result in the optimal outcome in patients with pancreas cancer and other cancers as well. Therefore, Dr. Nagathihalli feel there is significant potential of this treatment to contribute directly to the goal of doubling survival from pancreatic cancer by 2020. They have designed the experimental arms to test the efficacy of treatment at the early pancreatic cancer developmental stage of development as well as the late pancreatic cancer stage and also to evaluate tumor behavior once the treatment has been discontinued. Additionally, they have selected primary and metastatic model arms to evaluate effects of the regimen in different phenotypic subtypes.