The Scripps Research Institute Physical Sciences-Oncology Center (TSRI PS-OC) incorporates a trans-disciplinary effort from celebrated physicists and oncologists to pursue the mechanisms that regulate the survival of circulating tumor cells. These investigators will probe the biophysical factors implicated in the endurance of individual circulating tumor cells while in the blood stream and in their progression to metastatic disease. Fluid phase biopsies from epithelial cancers such as lung cancer will be employed to assess and model the physical attributes of these tumor cells over the course of the disease across various body compartments. In addition, this center will utilize highly sophisticated, quantitative physical science techniques to analyze patient samples in terms of cell size, mechanical properties and ultrastructural complexity. This unprecedented approach should deliver a rich database for further longitudinal statistical and mathematical analysis and yield much needed insight into the behavior, survival and destination of circulating tumor cells.
Principal Investigator: Peter Kuhn, Ph.D.
Senior Scientific Investigator: Kelly J. Bethel, M.D.
Collaborators: Billings Clinic, J. Craig Venter Institute, Oregon Health and Science University, Scripps Clinic, Scripps Translational Science Institute, University of California-San Diego, University of Southern California
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Peter Kuhn, Ph.D.
Peter Kuhn is an associate professor in the department of cell biology at The Scripps Research Institute in La Jolla, Calif. His research is focused on the development of a fluid biopsy for the diagnosis, prognosis and therapy management of breast, lung, colon, prostate and other tissue cancers. He is the principal investigator of the NIH NCI Physics Oncology Center on the 4-dimensional biopsy, investigating the physics and mathematics of cancer metastasis.
Since joining Scripps Research in 2002, Kuhn has focused his research on developing novel approaches to therapeutic and diagnostic development in cancer and viral infections. The goal of his research is to significantly contribute to making cancer a managed disease. Most recently his work in collaboration with Scripps investigator Ray has led to the discovery of the structure of the human β2 Adrenergic receptor. This is the first high resolution structure determination of a recombinantly produced human G-protein coupled receptor and this work was one of the top ten scientific breakthroughs of Science Magazine in 2007.
Making cancer a managed disease is the theme of research in the Kuhn Laboratory. Translational team science is the approach by which the laboratory is accomplishing its goals. Working side by side across the disciplines of physics, biophysics, cell biology, pathology and oncology is the daily life in the lab. The blood system is the body’s major highway system providing the nutrition to the primary cancer and providing a transport mechanism for cancer cells to migrate to distant sites. These so called circulating tumor cells are then programmed to initiate new tumor growth that eventually kills the patient. Finding and characterizing these cells early provides a new opportunity to monitor and characterize the cancer over time and tailor the treatment to the specifics of an individual’s cancer.
To learn more visit http://4db.us.
Kelly J. Bethel, M.D.
Dr. Kelly Bethel is the senior clinical investigator of the 4DB Center. She is a practicing hematopathologist in Scripps Clinic Medical Group and holds an adjunct appointment in cell biology at The Scripps Research Center, where in conjunction with the Kuhn lab she focuses her research on circulating tumor cells.
Dr. Bethel received her B.A. degree in English Literature from Yale University in 1986 and her M.D. from George Washington University School of Medicine in 1991. She completed an internship in pediatrics, a residency in Anatomic and Clinical Pathology, and subspecialty training in Hematopathology. Dr. Bethel is board certified in Anatomic and Clinical Pathology and Hematopathology.
Since 1999 she has been practicing hematopathology at Scripps Clinic and Green Hospital. In addition to her clinical practice, she is the Medical Director of the Blood Bank at Scripps Clinic/Green Hospital, the Program Director of the Scripps Hematopathology Fellowship, and participates in various translational research activities investigating anemia, low grade B-cell malignancies and myelodysplasia. She also holds a teaching faculty appointment at UCSD in the Department of Pathology.
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Project 1 – Cytophysics—The Mechanical Properties of Cancer Cells
Project Leaders: Owen McCarty (Oregon Health & Science University) and Paul K. Newton (University of Southern California)
Our overriding goal for Research Project 1 is to develop a quantitative model describing tumor cell dynamics and dissemination in the microcirculation. Meaningful output from our model is reliant upon the quality of the input variables: the physical and mechanical properties of cancer. However, surprisingly little quantitative information is known about the size, shape and feel of cancer in the fluid phase, therefore, the first step toward the development of a model of cancer in the metastatic phase will be to establish the fundamental physical parameters of cancer cells in the blood circulation. Access to a unique population of tissue samples from non-small lung cancer patients will provide us with a baseline against which to characterize the physical properties of CTCs.
Project 2 – Topology, Ecology, and Travel Strategies of Cancer Cells
Project Leaders: Peter Kuhn (The Scripps Research Institute) and Kelly Bethel (Scripps Clinic)
Research Project 2 focuses at the level of functionally relevant structural properties of cell populations, and grouping behaviors of cancer cells with other cells in their microenvironment, by taking a comprehensive sampling across the time and space heterogeneity of the tumor via solid and fluid biopsies. While the experimental program in Research Project 1 focuses on elucidating the physical properties of individual tumor cells and their internal cellular structure, the focus of Research Project 2 is to look outward from the individual cell. We will investigate the physical properties and morphologic characteristics of populations of tumor cells in various phases and spatial regions of the disease and characterize the grouping behaviors they exhibit in their unique blood microenvironment. Identifying similarities and differences among the various tumor cells populations will identify meaningful heterogeneity and thus lend insight into which tumor cells are important.
RP3 - Equations of Topology - Mathematical Modeling of Cancer Metastasis
Project Leader: Paul K. Newton (University of Southern California)
Newton's team is developing quantitative/computational models describing tumor cell dynamics and dissemination in the microcirculation through establishing the fundamental physical parameters of CTCs in the bloodstream. During the past year, the team developed stochastic models of intravasation and circulating CTCs as well as a metastatic progression model using a Markov chain/network framework. The model can be used for predictive metastatic development as the disease progresses, providing results in the form of probabilistic distributions (pdfs) that can be tailored to individual patients using initial state vectors. What drives the model dynamics is a “transition matrix” which allows our research team to experiment with different scenarios and predict or design outcomes.
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Core 1 - The Clinical Sample Core
Core Leader: Kelly Bethel (The Scripps Research Institute)
The Clinical Sample Core (CSC) brings together a team of medical oncologists, pathologists, and surgeons, who will be responsible for the preparation of all patient samples and the distribution of samples to each Research Project Investigator in a form factor that is suitable for the specific measurement.
Building Infrastructure for a Physical Sciences in Oncology Field:
Correlative science clinical trials: early access to the initial clinical data was provided to the entire PSOC network, which resulted in a number of oncologists and surgeons to ask specific clinical questions to be answered with the fluid biopsy. There are now 18 such studies underway at the Scripps Physics Oncology Center in collaboration with 15 clinical sites around the country. The questions are ranging from timing of onset of systemic disease as identified by the occurrence of circulating tumor cells to the correlation of imaging of the primary and fluid phase to specific biomarkers as these might correlate with drug response.
Pathology Boot Camp: Integral to the process of recognizing, studying and characterizing circulating cancer cells is recognizing cancer cells in their original birthplace in the primary tumor of the cancerous organ that is shedding these cells. Consequently, the Scripps PSOC has run a series of microscope tutorials to familiarize both biological scientists and physical scientists with the features of human cancers as they actually exist in the clinic and hospital. From demonstrations of actual biopsy needles, to whole tumor slice microanatomy, to microscopic features of tumors, their blood supply, and their cellular morphologies, our 'Pathology Boot Camps' have educated numerous cancer researchers as to the realities and opportunities in human cancer tissue research.
Outreach Efforts: Our results demonstrate that scientists, clinicians, and patients working together will make a difference in cancer research and ultimately make cancer a managed disease. We are regularly opening our laboratory to the community of patients, families and all interested parties to a “Night at the Lab”. During the last event, visitors were greeted with a small reception followed by presentations by our scientists and clinicians on our research with updates on the progress made as well as our gratitude for the contributions made by the cancer patients and their families whether it is by means of blood donor samples, monetary donations, or being an ambassador of the research work and getting the word out to community. After the presentations, smaller groups had the opportunity to visit the laboratory for a tour, which included the blood processing room, the high performance scanning systems where plated glass slides are imaged, the single-cell picking room and finally the data analysis and images station. Explanations were provided of the work involved and questions were answered as these came up.
In a similar outreach effort in January 2013 we had the opportunity to reach a philanthropic audience, which was made possible by a generous supporter from the San Diego community of our research. By means of a dinner party cruise, “Navigating Cancer Research”, hosted by the anonymous donor and The Scripps Research Institute, the opportunity was provided to learn more about the progress in personalized cancer care that is being made possible by the revolutionary collaborations between doctors, scientists and patients are leading us to disruptive innovation in cancer care. The presentations focused on what tomorrow will look like and how it is up to us individually to invest in this future for it to happen NOW. Towards the end of the presentations the lasting impression was summed up by what Dr. Kuhn said, “What we have seen is an example of unwillingness to sit on the sidelines, but instead grabbing the opportunity to really make a difference for ourselves, our loved ones, and future generations to come.” This event led to many meaningful follow-up conversations and meetings.
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