By applying new imaging technology and genetics, researchers will better understand tumor behavior and predict clinical outcomes
(February 11, 2005, Philadelphia, PA) – The University of Pennsylvania School of Medicine was recently selected to become a member of the National Cancer Institute's Mouse Models of Human Cancers Consortium (MMHCC). The MMHCC was established in 1999 to design and characterize mouse models that more accurately reflect the way that human cancers develop and respond to therapy. The research groups comprising the MMHCC at 24 lead sites connect more than 50 institutions in the US and abroadand focus on mouse models for cancers of major organ systems including prostate, breast, lung, ovary, skin, colon, brain, and the blood and lymph systems.
Lewis A. Chodosh, MD, PhD, Vice Chair, Department of Cancer Biology, Associate Investigator in the Abramson Family Cancer Research Institute, and Program Leader of the Breast Cancer Program at the Abramson Cancer Center, heads one of four MMHCC sites at which breast-cancer models are being developed and studied. Chodosh will oversee a $2.5 million, five-year program based at Penn that encompasses multidisciplinary research from six institutions in three countries. Chodosh's co-principal investigators are: Mitchell D. Schnall, MD, PhD, Associate Chair of Radiology at Penn; Robert D. Cardiff, MD, PhD, of the University of California, Davis; and William J. Muller, PhD, of McGill University.
The goal of the Penn group is to develop new conceptual and technical approaches for understanding the mechanisms of breast tumor progression and metastasis. To accomplish this, Penn researchers will employ a broad array of state-of-the-art cellular and molecular imaging techniques to analyze a series of novel, genetically engineered mouse models of breast cancer. "It's truly a multidisciplinary team effort, bringing together biologists with radiologists, nuclear chemists, physicists, pathologists, and computational biologists," says Chodosh. "This type of endeavor requires a group of scientists with a tremendous breadth of knowledge and expertise, which this grant has allowed us to assemble.
"Understanding cancer biology and response to therapy is so complex a challenge that it requires changing the paradigm in which biomedical research is performed," explains Chodosh. "Traditionally, biomedical research is performed by small groups of departmentally based specialists working in relative isolation. In contrast, the MMHCC is based on the premise that more rapid progress can be made towards curing cancer by bringing together scientists from multiple, disparate academic disciplines to work synergistically in an interdependent manner. Our group embodies that principle."
Specifically, the Penn MMHCC group will use a comprehensive array of sophisticated technologies – including positron emission tomography (PET), magnetic resonance imaging (MRI), computed tomography (CT), magnetic resonance spectroscopy (MRS), single photon emission computed tomography (SPECT), and ultrasound – to visualize and follow tumor cells in living animals from their origins to their eventual progression to distant metastasis and recurrence. The technology will also be used to assess tumor response to therapy and to predict clinical outcomes.
The mouse models for breast cancer to be used in this program are unique in that the researchers can follow the entire natural history of the disease in each animal – from initial onset to response to therapy, tumor dormancy and, finally, metastasis and recurrence. "This process may take two years in a given mouse, which is why using non-invasive imaging approaches to follow the course of disease is so valuable," explains Chodosh. "Overall, we are bringing imaging, genetics, and cancer biology to bear on these end-stages of breast cancer."
Advanced stages of tumor progression, characterized by resistance to therapeutic agents, metastasis, and tumor recurrence, are responsible for the majority of cancer deaths. However, while tumor progression constitutes a problem of unrivaled clinical importance, the underlying mechanisms are largely unknown. Shedding light on the molecular and physiological events that contribute to this process is a critical priority in cancer research.
"Genetically, we're trying to identify the regulatory molecules responsible for the ability of tumors to metastasize, recur, or remain in a dormant state," explains Chodosh. "Imaging permits us to ask such questions as: Can we predict what a tumor will do in its natural history? Will it metastasize? Will it recur? Will it respond to therapy? Will this drug work or should we move on to the next drug?"
For example, using PET, researchers have already shown that patients with a specific type of stomach cancer who respond to the drug Gleevec show a dramatic change in glucose metabolism within 48 hours of taking the drug. In this way, imaging has provided a vital and rapid indication about response to therapy and survival that can be used to make decisions about whether to change medication or not.
"With imaging you can look at metabolism, blood flow, and numerous other physiological indicators important in tumor biology," says Chodosh. "And, due to the widespread clinical use of non-invasive imaging, much of what we learn how to do in a mouse should be translatable to patients."
Additional key investigators in the Penn MMHCC group include Britton Chance, PhD; David Tuveson, MD, PhD; Jerry Glickson, PhD; Paul Acton, PhD; Joel Karp, PhD; Abass Alavi, MD; Chandra Sehgal, PhD; and Hank Kung, PhD, as well as Ruth Muschel, PhD, at The Children's Hospital of Philadelphia and John Condeelis, PhD, at The Albert Einstein College of Medicine.
Contact: Karen Kreeger
The Abramson Cancer Center of the University of Pennsylvania was established in 1973 as a center of excellence in cancer research, patient care, education and outreach. Today, the Abramson Cancer Center ranks as one of the nation's best in cancer care, according to U.S. News & World Report, and is one of the top five in National Cancer Institute (NCI) funding. It is one of only 39 NCI-designated comprehensive cancer centers in the United States. Home to one of the largest clinical and research programs in the world, the Abramson Cancer Center of the University of Pennsylvania has 275 active cancer researchers and 250 Penn physicians involved in cancer prevention, diagnosis and treatment.