Kenneth P. Olive, PhD
Our laboratory is dedicated to finding a cure for pancreatic cancer. We perform preclinical therapeutics trials using advanced genetically engineered mouse models of pancreatic cancer. With an average survival of less than six months, PDA is a uniquely lethal disease that is responsible for the deaths of over 35,000 people annually in the US. 90% of patients present with advanced disease and in most cases, the tumors are innately resistant to chemotherapy. There is great need for advances in the treatment of this disease.
The core of our laboratory is based on a preclinical trials infrastructure called the "Mouse Hospital". This effort seeks to treat mice with pancreatic cancer in exactly the manner that human patients are treated. Tumor volumes are tracked and quantified using advanced small animal imaging technologies such as high resolution ultrasound and optical imaging, and mice are enrolled into randomized therapeutics trials. Pharmacokinetic and pharmacodynamic analyses, functional imaging, microscopy, biochemistry and molecular biology techniques are employed to assess drug mechanisms and understand relevant signaling pathways. Ultimately, successful therapies will be translated into the clinical settling through our collaborations with the Pancreas Center of Columbia University.
Our recent work has focused on mechanisms of resistance to chemotherapy. Unlike many cancers, most pancreatic tumors exhibit primary (innate) chemoresistance rather than secondary (acquired) chemoresistance. By studying tissue perfusion in KPC mice, we learned that drug delivery is compromised in pancreatic tumors, resulting in insufficient drug levels within tumor tissues. We found that the stromal cells of pancreatic tumors participate in this process and identified a small molecule agent (an inhibitor of the Hedgehog pathway) that depletes stromal cells from the pancreatic tumors in KPC mice. This agent facilitated the delivery of chemotherapy to pancreatic tumors and prolonged the survival of KPC mice. (Science, 2009). Clinical testing of Hedgehog inhibitors is under way and will determine the success of this approach in humans.
Upcoming efforts will be focused both on further elucidating the mechanisms by which Hedgehog pathway inhibitors affect pancreatic tumors as well as evaluating additional novel agents. More basic efforts within our laboratory will focus on developing improved mouse models and identifying potential drug targets in pancreatic cancer.