Researcher’s Profile

Kenneth P. Olive, PhD

Director, Oncology Precision Therapeutics and Imaging Core (OPTIC) Shared Resource
Body: 

Kenneth P. Olive is an associate professor in the department of medicine and director of the Oncology Precision Therapeutics and Imaging Core (OPTIC) Shared Resource.

Dr. Olive’s research is dedicated to finding a cure for pancreatic cancer. The Olive laboratory performs 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 the 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.

Dr. Olive’s 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, they learned that drug delivery is compromised in pancreatic tumors, resulting in insufficient drug levels within tumor tissues. They 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 Dr. Olive’s laboratory will focus on developing improved mouse models and identifying potential drug targets in pancreatic cancer.

As director of the Oncology Precision Therapeutics and Imaging Core (OPTIC) Shared Resource, Dr. Olive helps to enable any HICCC investigator to generate novel personalized models from patient materials, carry out preclinical therapeutics studies, and access state-of-the-art small animal imaging including optical, ultrasound, micro CT, and high-field MRI.

Research Statement: 

I lead a multidisciplinary team of scientists and physicians at all levels of training who are devoted to the study of pancreatic cancer. We utilize human samples, advanced mouse models, tumor explant cultures, and computational techniques to identify and target critical tumor-specific vulnerabilities of pancreatic cancer. Specific research areas include: cancer metabolism, tumor-stroma-immune crosstalk, precision medicine, tumor-microbial interactions, and imaging. We develop questions in these areas with support from advanced systems biology techniques based on regulatory network analysis, and test our ideas using a suite of innovative translational approaches. In particular, our “Mouse Hospital” is a multidisciplinary infrastructure that integrates small animal imaging, surgery, radiology, treatment, pathology, pharmacology, molecular biology, and tissue sampling to enable the detailed interrogation of cancer phenotypes in vivo. Complementing my laboratory research, I have also built a large-scale translational core facility called the Oncology Precision Therapeutics and Imaging Core (OPTIC). This NCI designated shared resource provides both small animal imaging technology as well as a comprehensive translational therapeutics service to CUIMC.

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.

Publications: 

Badgley MA, Kremer DM, Maurer HC, DelGiorno KE, Lee H-J, Purohit V, Sagalovskiy IR, Ma A, Kapilian J, Firl CEM, Decker AR, Sastra SA, Palermo CF, Andrade LR, Sajjakulnukit P, Zhang L, Tolstyka ZP, Hirschhorn T, Lamb C, Liu T, Gu W, Seeley ES, Stone E, Georgiou G, Manor U, Iuga A, Wahl GM, Stockwell BR, Lyssiotis CA, Olive KP. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science. 2020; 368(6486)85-89. PMID:32241947

Eberle-Singh JA, Sagalovskiy I, Maurer HC, Sastra SA, Palermo CF, Decker AR, Kim MJ, Sheedy J, Mollin A, Cao L, Hu J, Branstrom A, Weetall M, Olive KP. "Effective delivery of a microtubule polymerization inhibitor synergizes with standard regimens in models of pancreatic ductal adenocarcinoma". Clinical Cancer Research. 2019; 25(18):5548-5560. PMID: 31175095

Maurer C, Holmstrom SR, He J, Laise P, Su T, Ahmed A, Hibshoosh H, Chabot JA, Oberstein PE, Sepulveda AR, Genkinger JM, Zhang J, Iuga AC, Bansal M, Califano A, Olive KP. Experimental microdissection enables functional harmonisation of pancreatic cancer subtypes. Gut. 2019; 68(6):1034-1043. PMID: 30658994