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Irving Cancer Research Center ( Audubon III )
Room 217A
1130 St. Nicholas Avenue
New York, NY   10032

Phone: 212-851-4678

-Division of Digestive and Liver Diseases
-Department of Pathology

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Kenneth Olive
Assistant Professor of Medicine and Pathology

Research Summary
Our laboratory studies the response of pancreatic tumors to therapeutic intervention. We perform preclinical trials in genetically engineered models to evaluate novel agents and study their molecular and mechanistic responses to treatment.

Research Activities
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.

Lab website: www.olivelab.org

Positions & Appointments
2010 - present Assistant Professor, Dept. of Medicine Columbia University Medical Center New York, NY
2010 - present Assistant Professor, Dept. of Pathology Columbia University Medical Center New York, NY
2010 - present Assistant Professor, Herbert Irving Comprehensive Cancer Center Columbia University Medical Center New York, NY

Education and Training
1994 - 1998 B.S. Biology Bucknell University, Lewisburg, PA
1998 - 2005 Ph.D. Biology Massachusetts Institute of Technology, Cambridge, MA
2005 - 2006 Postdoctoral Fellowship University of Pennsylvania, Philadelphia, PA
2006 - 2009 Postdoctoral Fellowship University of Cambridge/Cambridge Research Institute, Cambridge, England

Honors and Awards
Bernard L. Schwartz Designated Research Award in Pancreatic Cancer, from the American Gastroenterological Association

Selected Publications:
1. 3. Olive KP, Davidson CJ, Jacobetz MA, Honess D, McIntyre D, Madhu B, Goldgraben MA, Frese K, Caldwell ME, DeNicola G, Feig C, Gopinathan A, Combs C, Winter SP, Ireland H, Wang L, Rückert F, Grützmann R, Pilarsky C, Izeradjene K, Hingorani SR, Huang P, Da (2009) Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer
Science 324:1457-1461

2. Olive KP and Tuveson DA. (2006) The Use of Targeted Mouse Models for Preclinical Testing of Novel Cancer Therapeutics
Clin Cancer Res 12(18):5277-5287

3. Jackson EL* & Olive KP*, Tuveson DA, Bronson R, Crowley D, Brown M, Jacks T. (2005) The Differential Effects of Mutant p53 Alleles on Advanced Murine Lung Cancer Cancer Research 65(22):10280-10288

4. Olive KP, Tuveson DA, Ruhe ZC, Yin B, Willis NA, Bronson RT, Crowley D, Jacks T. (2004) Mutant p53 Gain-of-Function in Two Mouse Models of Li-Fraumeni Syndrome Cell 119:847–860

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