This Small Business Innovation Research (SBIR) Phase II project is to address the high lethality of pancreatic cancer. Screening has begun with Phase IB funding, of natural products from the Sonoran Desert that have produced other promising drug candidates, testing effects on human pancreatic cancer cells. The objective of Phase II is to develop a drug candidate that alters expression of selected pancreatic cancer-related genes and that kills pancreatic cancer cells that express those genes. The drug candidates will be developed using a personalized medicine approach. The gene expression profiles (or genomics patterns) for many different pancreatic cancer tumors will be matched to the effects on genomics produced by the drug. This personalized approach could translate directly to clinical trials to pre-select patients most likely to respond to the drug.
The broader impacts of this research are first to reduce deaths due to pancreatic cancer, which ranked fourth among the leading causes of cancer death with 35,240 deaths in the US in 2009. The 5-year survival rate for patients with metastatic disease is 1.8%. The societal impact and commercial value of targeting such a lethal disease are very high. Further, the personalized medicine approach to drug development will impact many oncology projects. The idea of matching each patient's genomics patterns with each drug that targets that pattern will be critical. Each kind of cancer is not one disease, but a wide spectrum of accumulated genomics changes that have to be addressed individually.
The ultimate goals of the Phase I and II grants were to identify and test a natural product drug for treating pancreatic cancer. We were able to find a plant extract with activity against pancreatic cells and were able to isolate a pure compound that was active. There was not a lot of material available so our collaborator searched for seed so more of the plant could be grown. Although this was successful for a previous grant (growth of a plant and isolation of a compound from the plant for treating prostate cancer), our field expert was not able to find seeds for this particular species, and he suggests that it may now be extinct. Our collaborator continues to search for the plant and if we are ever able to find seeds we will continue that part of the project. A fungal extract that was found to be positive was also used for fractionation. A series of compounds was found to be active and the structures were determined. However, these compounds were not produced by the fungus when regrowth was tried. Several growth conditions were tried but none were successful. Unfortunately, this can be a problem when isolating active compounds from fungal cultures. With permission from our program officer, we continued work with a compound found by our undergraduate students working under an REU award. The compound appeared to increase the amount of killing of pancreatic cells in the presence of gemcitabine (the drug used most commonly for treating pancreatic cancer). Several analogs were tested for synergistic activity and one was chosen to be tested with gemcitabine in a mouse model of pancreatic cancer. Drug dosages were found in which each drug by itself did not kill the mice or completely eradicate the tumors. Then a combination therapy was tested in a mouse xenograft model. Unfortunately, although each compound by itself was moderately effective in killing the tumors and was not toxic at any concentration tested, the combination therapy was toxic to the mice.