Pancreatic cancer research

Pancreatic cancer is presently the fourth most lethal cancer in the United States and by 2030 is predicted to become the second-leading cause of cancer-related death, surpassing breast, prostate and colorectal cancers. The reasons for the high mortality associated with pancreatic cancer are a lack of effective treatments and the inability to predict the disease in advance. We have been studying the role of microRNAs in the development of pancreatic cancer and as a means for early detection. Ongoing projects include the discovery and validation of microRNAs circulating in the bloodstream as biomarkers of disease. We are also studying the very early stages of the disease by looking at genes and microRNAs that are involved in the acinar to ductal metaplasia, the process by which digestive enzyme secreting acinar cells transdifferentiate to cells with an epithelial morphology. Many believe that this is the earliest type of pancreatic precursor lesion and identifying genes or microRNAs that are involved in the regulation may lead to new treatments. microRNA knockout mouse models of pancreatic cancer are under development to investigate the tumor suppressive roles of specific microRNAs in the development of the disease. Another project involves small molecule drug screening to discover compounds that can de-repress silenced microRNAs with the aim of causing de-differentiation of the malignant phenotype.

Liver cancer therapeutics and biomarker discovery

Like pancreatic cancer, liver cancer or hepatocellular carcinoma is a devastating disease with very few treatments options. There is presently only one drug (sorafenib, Nexavar®) that is FDA approved to treat advanced hepatocellular carcinoma, however the clinical response to this drug is quite modest. We are currently studying microRNAs and small molecule drugs as new treatment regimens for advanced hepatocellular carcinoma. microRNAs are often overexpressed or under expressed in the tumor relative to the normal tissue. We are using synthetic oligonucleotides to inhibit overexpressed microRNAs or replenish under expressed microRNA for those that are decreased in the tumor ( We are also examining novel mTOR pathway inhibitors as a means to treat sorafenib resistant and insensitive liver tumors.


Extracellular vesicles as drug delivery systems

Oligonucleotide therapy holds great potential for the treatment of cancer and other diseases. Major drawbacks include effective delivery in the bloodstream and targeting and uptake by the tumor. We are presently developing extracellular vesicles as novel systems to deliver therapeutic oligonucleotides to treat hepatocellular carcinoma. Extracellular vesicles (exosomes, microvesicles) are small (~ 100 nm diameter) vesicles of endocytic origin that are naturally produced by many cell types and are released into several bodily fluids including the bloodstream. Extracellular vesicles contain a variety of cargo including DNA, RNA, microRNA and protein. Due to the cell membrane and effective packaging, extracellular vesicles provide a stable environment for the cargo while circulating in the bloodstream. We are presently engineering extracellular vesicle producing cells to display membrane targeting peptides on their surface and also to have the producing cells direct endogenously expressed therapeutic microRNAs as a treatment for liver cancer. In this manner the producing cells are not only making the targeted delivery system but also the microRNA therapeutic. Plans are for large scale up and in vivo studies are in the works.


Exosome Biogenesis















Cell surface undergoes endocytosis, drawing in surrounding surface molecules and structures.

Within the cell, the endosome pinches off and travels within the cell cytoplasm.

MicroRNA formation begins in the nucleus, and the process is completed outside of the nucleus.  The endosome is bathed in a shower of microRNA complexes.

The endosome undergoes further endocytosis to produce exosomes within the endosome, and microRNA complexes are incorporated into the newly formed exosomes.  Surface molecules and structures originally present on the cell are now on the surface of the newly formed exosomes.





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