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Professor and Vice Chair
Department of Surgery
Washington State University,1980, Ph.D.
Pancreatic Cancer Research
Pancreatic cancer is a devastating disease with a poor prognosis
and is the fourth leading cause of cancer-related death in
the US. Every year, more than 36,000 Americans succumb to
this disease. Pancreatic cancer is so difficult to treat because
its cells are highly resistant to apoptotic cell death. Our
laboratory is interested in the role played by heat shock
proteins in the pathophysiology of this resistance. In recent
studies published in Cancer Research, we demonstrated that
HSP70 is overexpressed in pancreatic cancer cells and that
its inhibition leads to apoptotic cell death. Inhibiting HSP70
expression is also very effective at reducing the growth of
pancreatic tumors in orthotopic models of pancreatic cancer,
where it markedly reduces loco-regional spread. We are currently
developing strategies to extend these findings into the clinical
setting, which include creating novel pharmacologic inhibitors
of HSP70 expression as well as developing nanoparticles capable
of delivering HSP70 siRNA selectively to cancer tissue. In
other studies, we are evaluating novel strategies (also involving
death receptors and HSP70) to treat otherwise non-responsive
and very aggressive pancreatic tumors.
Another important area in pancreatic cancer research is the mechanism by which HSP70 inhibits apoptosis in cancer cells. We have demonstrated that HSP70 inhibits apoptosis by two independent yet simultaneous means: by attenuating intracellular calcium and by stabilizing the lysosomes. We are currently investigating how HSP70 influences calcium homeostasis and lysosomal stability. We are also evaluating various naturally-occurring compounds as potential therapies for this deadly disease.
Pancreatitis is the other devastating disease of the exocrine pancreatitis for which currently there are no treatments other than supportive care. Like that of pancreatic cancer, the pathophysiology of pancreatitis is not well understood. While it is generally believed that the premature activation of digestive enzyme zymogens in the pancreatic acinar cells initiates the onset of pancreatitis, the intraacinar activation by which this occurs is still under intense investigation. We have set forth a colocalization hypothesis, which proposes that during the early stages of pancreatitis, digestive enzyme zymogens and lysosomal enzymes are colocalized in acinar cells, and that this results in activation of trypsinogen by the lysosomal hydrolases – particularly cathepsin B. Recent findings from our group suggest that HSP70 is protective in pancreatitis and that its upregulation should be beneficial against pancreatitis. One of the high-priority areas in our laboratory is to study the mechanisms by which HSP70 protects against pancreatitis and the ensuing inflammatory response.
Another area of interest in our group is to ascertain and evaluate the mechanisms and treatment strategies for the excruciating pain associated with the pancreatic diseases, with particular emphasis on opioid receptors.
Last modified on: June 4, 2008