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Translational Pancreatic Cancer Research

Principal Investigator
Reber, Howard A. M.D.
Hines, Joe M.D.

Contact Phone Number
(310) 825-4976

Director Bio

Dr. Reber is a graduate of the University of Pennsylvania School of Medicine where he remained to complete his general surgery residency training and a gastrointestinal physiology fellowship. He served on the faculty at the University of California, San Francisco until 1978, when he moved to the University of Missouri. Dr. Reber returned to California in 1986 upon joining the faculty at UCLA as Professor and Chief of the Surgical Service at Sepulveda VA Medical Center. In 1996, Dr. Reber assumed leadership of the Gastrointestinal Section of the Division of General Surgery at UCLA. Dr. Reber is recognized as an international authority on pancreatic physiology. He has developed an active laboratory in pancreatic disease and more recently, in pancreatic cancer. Dr. Reber's investigations of pancreatic blood flow and pH as determinants in the etiology of human pancreatitis have influenced further research developments in pancreatic disease across the United States. He is the Associate Editor for Pancreas and he serves on the editorial boards of three major journals in gastroenterology and pancreatology

Dr. Hines graduated at the top of his medical school class from the University of Oklahoma in 1990. He completed his general surgery residency training at UCLA in 1997. During his residency, Dr. Hines was recognized as Outstanding Second Year Surgical Resident and subsequently as the Outstanding Cardiothoracic Resident. In July 1997, Dr. Hines joined the full-time faculty in the UCLA Division of General Surgery. He is the author of twenty-eight papers, primarily in the area of intestinal absorption. His clinical interests span the full range of general surgery and include gastrointestinal and endocrine diseases, as well as trauma and critical care.

Introduction

Pancreatic cancer is the fourth most common cause of cancer death in the United States today, and it is the second most common cause of death from malignancies of the gastrointestinal tract. There are about 27,000 new cases a year in the USA, and almost all of the patients eventually die from the disease. By the time the diagnosis is made, the tumor has already progressed to the point where surgical resection is impossible in most patients. In those where resection can be performed, the five year survival rate is only about 10%, and about half of the patients who do live for five years still die from recurrent cancer. Thus, this disease is truly one of the worst malignancies known to mankind.

Early in 1997, Ronald S. Hirshberg was diagnosed with pancreatic cancer, and, in spite of all of the efforts to treat it, he succumbed to the disease eight months later. He was 54 years old. Thus, the Ronald S. Hirshberg Program In Translational Pancreatic Cancer Research was established in his memory by his wife, Agi Hirshberg. Mrs. Hirshberg says, "It is my mission to do what I can to give answers and hope to families afflicted with this dreadful disease. There are no survivors to take on this task." The Program, which resides within the Section of Gastrointestinal Surgery of the Division of General Surgery, is dedicated to those goals. The laboratories are situated on the second floor of the Gordon and Virginia McDonald Research Building on the UCLA Health Sciences campus. Other laboratory personnel include Mark Sawicki, MD, Assistant Professor of Surgery, UCLA School of Medicine; Hubert Hotz, MD, Research Fellow in Surgery, Benjamin Franklin University, Berlin, Germany; and Peter Buchler, MD, Research Fellow in Surgery, University of Bern, Bern, Switzerland.

Research

The research program is pursuing a number of different projects. The major ones involve 1) the creation of a clinically relevant animal model for the study of pancreatic cancer; 2) the study of various nutritional and metabolic factors as they relate to pancreatic cancer and; 3) an investigation of the effects of hypoxia on the growth characteristics and metastatic potential of pancreatic cancer.

Animal Model for Pancreatic Cancer

Most animal models of the disease which actually use human pancreatic cancer cells employ nude mice into which tumor cells are injected subcutaneously. The tumors grow in the subcutaneous tissue, and a variety of studies, i.e. investigations of tumor biology, growth, response to therapeutic agents, can be performed. A major drawback of such models is the fact that the transplanted tumors grow in a milieu drastically different from the human pancreas in which they arose, which makes the clinical relevance of their response to treatment and general biological behavior suspect. Moreover, unlike pancreatic cancers in patients, these tumors rarely metastasize.

The Hirshberg Program is creating an animal model in nude mice in which human pancreatic cancer cells are introduced into the mouse pancreas. Clones of cells which have the propensity to metastasize to the liver are isolated, cultured, and then introduced again into the pancreas of other nude mice. The goal is to create a clinically relevant animal model of pancreatic cancer, derived from a human tumor, with a high metastatic potential.

Nutrition and Pancreatic Cancer

Most patients with pancreatic cancer lose an extraordinary amount of weight in the weeks before their disease is diagnosed. There is some evidence that the tumor itself is responsible for alterations in normal metabolism, and that this profound catabolic response is the result. The impaired nutritional state which may follow can compromise the patients' ability to withstand major surgery, or the chemotherapy and/or radiation that may be part of the treatment regimen. One aspect of the nutrition-related research will be to characterize the factor(s) responsible for the catabolic activity, and to elucidate the cellular processes that are affected.

Some patients with pancreatic cancer who are fortunate enough to undergo surgical resection may suffer a variety of gastrointestinal complaints (e.g., diarrhea, nausea, early satiety, vomiting) as long term side effects of the surgery. These may compromise the quality of life; they also may interfere with the administration of adjuvant therapy. The nutritional abnormalities that result from pancreatic resection have never been adequately characterized. A second aspect of the nutrition studies will fully characterize the nutritional and metabolic consequences of the standard Whipple pancreaticoduodenectomy and its pylorus preserving modification.

These and other studies that are investigating the effects of dietary lipid intake on the growth and cell biology of pancreatic cancer are being done in collaboration with Drs. David Heber and Vay Liang W. Go in the UCLA Center for Human Nutrition.

Hypoxia and Pancreatic Cancer

Prior studies from this laboratory have shown that chronic pancreatitis is associated with an impairment of pancreatic blood flow. The pancreatic tissue is ischemic, the tissue pH is acidotic, and the tissue oxygen tension is reduced. Since almost all pancreatic cancers are surrounded by a zone of chronic pancreatitis, this lab has hypothesized that pancreatic cancers also develop in an hypoxic environment as well. This may be important because it is known that other tumors which exhibit low tissue pO2 are particularly resistant to treatment, exhibit an increased propensity to metastasize, and develop genetic changes which provide the malignant cells with a distinct growth advantage.

For these reasons, a variety of studies are being pursued which will characterize the effects of hypoxia on pancreatic cancer cell growth, and the expression of a number of genes which are known to be inducible by hypoxia. The effects of these genetic changes on cell growth, metastatic potential, and apoptosis are being investigated.

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