H. Lee Moffitt Cancer Center & Research Institute Physical Sciences-Oncology Center's (MCC PS-OC) mission is to assemble a multi-disciplinary group of scientists to incorporate physical science concepts into cancer biology and oncology. Cancer progression can be categorized into several stages defined by markedly diverse temporal and spatial scales - carcinogenesis, invasive cancer, and clinical therapy. Each of these phases of cancer will be explored by this center. In particular, in the investigation of carcinogenesis, these investigators propose that both genetic alterations and microenvironmental selection pressures must be deciphered to impede somatic evolution. Furthermore, this group of prominent theoreticians, cancer biologists and clinicians will apply mathematical modeling to determine if oncogenesis is regulated by the escape from tissue homeostasis, a fresh perspective on the unfolding of cancer. These investigators have a long history of expertly drawing on mathematical modeling to shed light on a variety of complex biological problems in cancer and should provide further insight into the complex problems associated with cancer.
Principal Investigator: Robert A. Gatenby, M.D.
Senior Scientific Investigator: Robert J. Gillies, Ph.D.
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Collaborators: Oxford University, University of Illinois, Chicago, University of Washington, Northwestern University Feinberg School of Medicine, University of South Florida, Vanderbilt University Medical Center
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Robert A. Gatenby, M.D.
Robert A. Gatenby, MD is the Chairman of the Department of Radiology at H. Lee Moffitt Cancer Center and Co-Director of the Cancer Biology and Evolution Program. He joined Moffitt in 2008 from the University of Arizona where he was Professor, Department Radiology and Professor, Department of Applied Mathematics since 2000. He received a B.S.E. in Bioengineering and Mechanical Sciences from Princeton University and an M.D. from the University of Pennsylvania in 1977. He completed his residency in radiology at the University of Pennsylvania where he served as chief resident. Bob remains an active clinical radiologist specializing in body imaging. While working at the Fox Chase Cancer Center after residency, Bob perceived that cancer biology and oncology were awash in data but lacked coherent frameworks of understanding to organize this information and integrate new results. Since 1990, most of Bob's research has focused on exploring mathematical methods to generate theoretical models for cancer biology and oncology. His current modeling interests include: 1. the tumor microenvironment and its role in tumor biology. 2. evolutionary dynamics in carcinogenesis, tumor progression and therapy. 3. information flow in living systems and its role in maintaining thermodynamic stability.
Robert J. Gillies, Ph.D.
Professor Gillies is Chairman of the Department of Cancer Imaging and Metabolism; Vice-chair for research in the Department of Radiology and Scientific Director of the Small Animal Imaging Lab (SAIL) and Image Response Assessment Team (IRAT) shared services at the Moffitt Cancer Center.
Prof. Gillies received his PhD in Zoology from University California, Davis in 1979 and did post-doctoral work on in-vivo Magnetic Resonance Spectroscopy, first at the Bell Labs (Summit, NJ) and then at Yale University. He joined the faculty at Colorado State University as an Assistant Professor of Biochemistry in 1982. He moved to the University of Arizona as an associate professor with tenure in 1988 to establish a research program in biomedical MR spectroscopy, which over the years grew to include biomedical MRI. While at Arizona, he was director of the Cancer Imaging program and co-founder of the Advanced Research Institute for Biomedical Imaging, ARIBI. He relocated to Moffitt in 2008 as part of a major investment in radiology and imaging research.
Prof. Gillies has received numerous local, national and international awards for his teaching and research, including Researcher of the Year 2012 (Moffitt Cancer Center), Furrow award for innovative teaching (U. Arizona), the Yuhas award for radiation oncology research (U. Penn) and the TEFAF professorship (U. Maastricht) a named Fellow of the International Society for Magnetic Resonance in Medicine and the distinguished Basic Scientist award from the Academy for Molecular Imaging. Dr. Gillies' vision for the Moffitt imaging initiative includes development of new applications to diagnose, predict and monitor therapy response using noninvasive imaging. This work spans a breadth from molecular and chemical work, to animal studies and to human clinical trials and patient care. Dr. Gillies also leads a post-doctoral/resident training program in cancer imaging. His research is focused on functional and molecular imaging of cancer, specifically with an emphasis on the use of imaging to inform evolutionary models of carcinogenesis and response to therapy.
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Project 1 - The Physical Microenvironment in Somatic Evolution of the Malignant Phenotype
Project Leader: Alexander (Sandy) Anderson (H. Lee Moffitt Cancer Center)
Project 1 is focussed on using an integrated experimental, clinical and theoretical approach to examine the role of microenvironmental factors in driving melanoma initiation and progression. We believe that in order to understand malignant development we need to better understand normal development and have therefore implemented a multiscale mathematical model of normal skin (vSkin). The model focuses on important cellular and microenvironmental variables that regulate homeostatic interactions among keratinocytes, melanocytes and fibroblasts,which are the key components of the skin. Using our virtual skin model, we are systematically investigated the effects of disrupting interactions between melanocytes, keratinocytes, fibroblasts and the microenvironment in order to better understand what drives melanoma initiation. In parallel we are using both 3D cell culture and organotypic culture methods to motivate and test model predictions.
Figure Legend: Left figure shows the vSkin model domain with its key cell types: keratinocyte, melanocyte and fibroblast. The gray color represents the density of extracellular matrix at each node in the domain, i.e., darker gray represents denser matrix. Right figure is a photomicrograph showing a mature 3D organotypic culture of normal skin.
Normal skin development
Senescent fibroblast infiltration, leading to nevus formation
Project 2 - The Physical Environment in Cancer Invasion
Project Leader: Robert Gillies (H. Lee Moffitt Cancer Center)
This project focuses on the role of the tumor physical microenvironment in tumor growth and invasion and as a potential target for therapy with components in both basic science and clinical translation. In the basic science studies, we focus on the interaction of the organic components of the microenvironment, particularly angiogenesis and blood flow, with the physical parameters such as oxygen, glucose, and H+ concentrations. In the clinical translation, we center much or our research efforts on clinical trials investigating the role of increased systemic buffering capacity (through oral ingestion of sodium bicarbonate) in 2 settings: First, a study on the role of systemic buffers in relieving cancer-related bone pain. Second, a Phase 1/2 study that will add an escalating dose of oral buffer (sodium bicarbonate) to standard of care therapy (gemcitabine) in patients with metastatic or unresectable pancreatic cancer.
DCIS specimen showing tumor growth away from the basement membrane into the lumen with necrosis in the region of maximal distance from the membrane.
Theoretical model of diffusion-reaction kinetics of glucose, oxygen and acid as tumor proliferation carries in-situ tumor cells progressively further from the basement membrane.
Project 3 - Clinical Imaging and the Tumor Physical Microenvironment
Project Leader: Kristin Swanson (Northwestern University Feinberg School of Medicine)
Project 3 focuses on additional clinical translation research by scaling up current models applied to the tumor physical microenvironment to tissue-level models that can be applied to clinical cancers. Mathematically this project will focus on development of a clinical-scale model for malignant progression of brain tumors based on the combination of physical and organic microenvironment as described above. The goal is to develop models of human cancers that can be parameterized for individual patients through clinical imaging characteristics. In addition, the models will be used to predict therapeutic outcomes and those predictions tested against subsequent clinical imaging.
Using our PIHNA mathematical model connecting anatomic tumor growth kinetics with the microenvironment, we have been able to generate patient-specific simulations of a right temporal glioblastoma (GBM) showing excellent predictive agreement with the patient’s actual clinical MRI and FMISO-PET (hypoxia) images. Top: actual patient images (the MRIs serve as inputs to parametrize the PIHNA mode), Bottom: simulated patients images predicted using the actual patient MRI images as inputs. (No data from the actual patient FMISO-PET were used, rather, the model predicted simulated FMISO-PET (and associated hypoxia map) are predicted and validated by their close comparison with the actual FMISO-PET images.
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Core 1 - Computation/Mathematics Core
Core Leader: Alexander (Sandy) Anderson (H. Lee Moffitt Cancer Center)
The central premise of this PS-OC and the IMO is that cancer is a complex, multi-scale, adaptive dynamical system. Mathematical models are necessary to bridge the temporal and spatial scales ranging from molecular through organism-level processes. However, each scale also presents different challenges in measuring and modeling system dynamics that must be understood and addressed.
Core 2 - Small Animal Imaging Core
Core Leader: Robert Gillies (H. Lee Moffitt Cancer Center)
Understanding the multiscale dynamics of the physical microenvironment in cancer and its role it tumor biology requires both measurement of key cellular and environmental parameters and spatial and temporal variations in those parameters. Imaging is the key enabling technology in bridging the mathematical models and tumor biology. The Small Animal Imaging Laboratory includes the following technologies: a Varian 7T 30 cm horizontal bore MR system; a Hypersense hyperpolarizer adjacent to MR system; two IVIS bioluminescence fluorescence imaging systems (models 100 and 200); a VEVO 2200 phased array multi-frequency ultrasound system; a homemade beta imager, which can perform in vivo autoradiography in living mice with window chambers; and a Nikon 5400 multispectral LSC system with heated stage for intravital microscopy of window chambers.
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