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Dana-Farber Cancer Institute

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Dana-Farber Cancer Institute


Center Summary

Dana-Farber Cancer Institute Physical Sciences-Oncology Center (DFCI PS-OC) will intertwine the physical sciences with cancer biology and oncology by engaging evolutionary theory to address several critical issues concerning modern cancer research. Moreover, this center aspires to institute evolutionary modeling of cancer as a new field of study. To accomplish these goals, the center has brought together an acclaimed group of scientists from the fields of theoretical biology, cancer biology, oncology, physics and engineering. Iterative modeling will be employed to study the evolution of brain, lung, and hematopoietic tumors. Additionally, these investigators will draw on experimental data to tweak the evolutionary models that are formulated. One major evolutionary focus of this center will be to resolve which cell serves at the cell of origin for brain and hematopoietic tumors. Knowledge of the cells that initiate and drive cancer progression is critical for determining treatment options and will advance the struggle against cancer.

Principal Investigator: Franziska Michor, Ph.D.

Senior Scientific Investigator: Eric C. Holland, M.D., Ph.D.


Collaborators: City College of New York, Memorial Sloan-Kettering Cancer Center, Vanderbilt University

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Image of Franziska Michor, PhD

Franziska Michor, Ph.D.
Dr. Franziska Michor is the Principal Investigator (PI) of the PS-OC. Dr. Michor is an Associate Professor of Computational Biology in the Department of Biostatistics and Computational Biology at the Dana-Farber Cancer Institute, and in the Department of Biostatistics at the Harvard School of Public Health. Dr. Michor obtained her undergraduate in mathematics and molecular biology from the University of Vienna, Austria, and her PhD from the Department of Organismic and Evolutionary Biology at Harvard University. Afterwards, she was awarded a fellowship from the Harvard Society of Fellows, which she used to perform research at the Dana-Farber Cancer Institute. From 2007 until 2010, she was an Assistant Professor in the Computational Biology Program at Memorial Sloan-Kettering Cancer Center. Dr. Michor is the Principal Investigator of an NIH R01 and has been the recipient of the Theodosius Dobzhansky Prize of the Society for the Study of Evolution, a Gerstner Young Investigator Award, and a Leon Levy Young Investigator Award. Dr. Michor's laboratory investigates the evolutionary dynamics of cancer initiation, progression, response to therapy, and emergence of resistance. Additionally to being the PI of the PS-OC, Dr. Michor is also a project leader of projects 2 and 3 and an investigator of project 1.

Image of Eric Holland, MD, PhD

Eric C. Holland, M.D., Ph.D.
Dr. Eric C. Holland, MD, PhD is the Senior Co-Investigator (SI) of the PS-OC. Dr. Holland has been on the faculty at MSKCC since December of 2000. He is currently an Attending Surgeon in the Department of Neurosurgery, an Attending in the Departments of Neurology, and a Member of SKI's Department of Cancer Biology and Genetics. He holds the Emily Tow Jackson Chair in Oncology. In addition, he is the Vice Chairman of Translational Research for the Department of Surgery, and Director of the BTC which supports basic and translational research in brain tumor biology and its application to clinical trials. Dr. Holland is the Principal Investigator of several NIH grants including two RO1's, a U54 program grant on the tumor microenvironment, and was previously the PI of a P20 SPORE planning grant in brain tumors at MSKCC. In addition, he has been a member of the Mouse Models of Human Cancer Consortium Steering Committee since its inception, and has served on multiple committees and advisory boards at the NIH involving brain tumors and brain tumor biology. Dr. Holland's laboratory focuses primarily on the understanding of the molecular mechanisms underlying the pathogenesis of CNS tumors and in modeling these cancers in the mouse. To this end, the laboratory pioneered the use of RCAS/TVA mediated somatic cell gene transfer in the study of multi-step tumorigenesis in the mouse. This laboratory is developing bioluminescence and anatomical imaging strategies for tumors that allow non-invasive visualization of biologic activities in the tumors. In addition, these models are being used in preclinical trials of novel drugs targeting the signaling pathways that cause the disease. Additionally to being the SI of the PS-OC, Dr. Holland is also a project leader of project 2 and an investigator of project 1 and 3.

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Rameen Beroukhim
Dr. Rameen Beroukhim is Assistant Professor of Medicine at Harvard Medical School and in the Departments of Medical Oncology and Cancer Biology at the Dana-Farber Cancer Institute and is a practicing oncologist in the Center for Neurooncology at the Dana-Farber. He is also an Associate Member of the Broad Institute. His primary interest is in understanding the heterogeneity observed across cancers through understanding their varied somatic genetics. Much of Dr. Beroukhim's work has focused on copy-number changes in cancer and on the development of computational approaches to large genomic datasets. An example is the Genomic Identification of Significant Targets In Cancer (GISTIC) algorithm, which distinguishes driver from passenger copy-number changes and identifies genes likely to be targeted by the driver events. Dr. Beroukhim has applied these approaches to thousands of cancer copy-number profiles across a range of diseases. These efforts have identified novel amplified oncogenes such as MCL1 and BCL2L1, have identified prognostic indicators in endometrial and ovarian cancers, and have identified predictors of pathway dependency in several cancer types such as glioblastoma and renal cancer.

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Timothy A. Chan
Dr. Timothy A. Chan is an Assistant Member and Attending Physician at the Memorial Sloan Kettering Cancer Center (MSKCC) and Assistant Professor at the Weill Cornell School of Medicine. He is PI of a cancer genetics laboratory and is an expert in the study of tumor suppressor genes. Dr. Chan has received an MD, a PhD in cancer genetics, completed a residency in Radiation Oncology, and a fellowship in cancer genomics. The Chan laboratory specializes in using genomic analysis to characterize the role of tumor suppressors in oncogenesis and in using multiple approaches for the functional study of cancer genes. These approaches include large-scale analyses, functional genomics, epigenomics, biochemical and molecular analyses, and mouse modeling. The lab has a special interest in deciphering the mechanisms underlying metastasis.

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Subhajyoti De
Dr. Subhajyoti De, is a tenure-track assistant professor at the Department of Medicine, University of Colorado School of Medicine. Dr. De did an integrated BS and MS in engineering from the Indian Institute of Technology, Kharagpur, India before completing a PhD from the University of Cambridge, UK in evolutionary human genomics. Next, as a Fellow of King's College, Cambridge and then as a Human Frontier Science program Fellow at Dana Farber Cancer Institute, he worked on on mutational patterns in cancer genomes. Dr. De's primary research interests are analyzing genomic and epigenomic abnormalities in different cancer types using genomics and bioinformatics approaches.

Image of Rong Fan, Ph.D.

Rong Fan, Ph.D.
Dr. Rong Fan, PhD, is Assistant Professor of Biomedical Engineering at Yale University. Dr. Fan received his PhD in chemistry from University of California at Berkeley. His graduate work involves the development of novel nanofluidic transistors for single molecule detection and ion transport control. Afterwards, he went on to take a postdoctoral associate position in Professor Jim Heath's laboratory in NanoSystems Biology Cancer Center at CalTech, where he developed a high-density barcode microarray for multiplexed protein measurement on minute amounts of whole blood or even single antigen-specific T cells from cancer patients. His current research focuses on the development of microfluidic technologies for single cell proteomic and epigenomic analysis and the application of these technologies to investigate tumor microenvironment and tumor heterogeneity. He is the recipient of numerous awards including the MRS Graduate Student Gold Award, the NCI Howard Temin Pathway-to-Independence award, the Bill&Melinda Gates Foundation GCE award. Dr. Fan anticipates developing five single cell platforms to facilitate all three projects in the DFCI PSOC. These platforms include: (1) single cell secretomic profiling, (2) single cell phospho-protein profiling, (3) single cell whole genome amplification, (4) single cell epigenome amplification and (5) high-content laser imaging cytometry.

Image of Jasmine Foo, Ph.D.

Jasmine Foo, Ph.D.
Dr. Jasmine Foo, PhD, is an Assistant Professor of Mathematics at the University of Minnesota-Twin Cities. Dr. Foo obtained her undergraduate degree in mathematics and physics from Brown University. Following that, she was awarded a US Department of Energy graduate fellowship to pursue a doctorate in Applied Mathematics at Brown. There, she worked on the development and analysis of stochastic spectral methods for partial differential equations with parametric uncertainty. Afterwards, Dr. Foo joined the lab of Dr. Franziska Michor as a postdoctoral research associate, where she worked on the theory of cancer evolution. Dr. Foo's primary interests are in the development and analysis of mathematical models to study the evolution of diversity and drug resistance in tumors. She is interested in the application of these models to improve treatment strategies in the clinic. She is also interested in the dynamics of cancer initiation from healthy tissue and the role of mutational landscapes and lifetime distribution on these processes.

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Mithat Gönen, Ph.D.
Dr. Mithat Gönen, PhD, is an Associate Attending Biostatistician the Department of Epidemiology and Biostatistics at Memorial Sloan-Kettering Cancer Center. Dr. Gönen's clinical collaborations focus on surgical treatment of gastrointestinal and hepatobiliary cancers. He also has a long-standing collaboration with Nuclear Medicine which encompasses the development of Positron Emission Tomography (PET) in cancer diagnosis and prognosis. Most of Dr. Gönen's methodological research originates from these collaborations, including building, assessing and comparing predictive models, as well as the design and analysis of radiologic studies with clustered data. He also has an interest in developing Bayesian methods for clinical trials and observational data. He recently published a book on the use of receiver operating characteristic (ROC) curves using SAS. Dr. Gonen is a member of the program committee and the faculty of AACR/ASCO Vail Workshop on Methods in Clinical Cancer Research and he is on the editorial boards of Clinical Trials: Journal of the Society of Clinical Trials and Gastrointestinal Cancer Research. He is serving the American Statistical Association as the president of the Committee on International Relations. He serves as the Biostatistical Consultant of the PS-OC.

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Kevin Leder, Ph.D.
Dr. Kevin Leder, PhD, is an assistant professor in Industrial and Systems Engineering at the University of Minnesota. Prior to this he worked as a post-doc in the lab of Dr. Franziska Michor at Dana Farber Cancer Institute and Memorial Sloan Kettering. In addition he spent a year working in the Industrial Engineering department at Columbia University. He obtained his PhD in applied mathematics from Brown University where he worked on the characterization and efficient simulation of rare events in stochastic processes. He is currently interested in the design of optimal cancer treatment strategies that are robust to noisy parameter values, and incorporate knowledge of the high levels of intra-tumor diversity. In addition he is interested in the analysis and use of stochastic simulation to find solutions to optimization problems with noisy parameters.

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Ross L. Levine, M.D.
Dr. Ross L. Levine, M.D., is a physician-scientist, named to the incumbent of a Geoffrey Beene Junior Faculty Chair. Currently, he is an Assistant Member in Memorial Hospital's Human Oncology and Pathogenesis Program and also holds an appointment on the Leukemia Service in the Department of Medicine at MSKCC. While working in the laboratory of Gary Gilliland at Harvard Medical School, Dr. Levine, along with three other groups, identified JAK2 mutations in patients with polycythemia vera, essential thrombocytosis, and myelofibrosis. His laboratory focuses to improve the understanding of the genetic basis for activation of signal transduction pathways in myeloid malignancies, and to use this knowledge to improve therapies for patients with these disorders. Dr. Levine is an investigator of projects 1 and 2.

Image of Ingo Mellinghoff, M.D.

Ingo Mellinghoff, M.D.
Dr. Ingo Mellinghoff, M.D., is an Assistant Member in the Human Oncology and Pathogenesis Program and the Department of Neurology. Dr. Mellinghoff's research program focuses on the development of new diagnostic and therapeutic approaches for cancer with a focus on signal transduction and a particular disease focus on glioblastoma. His goal as physician-scientist is to reduce the individual and societal burden of cancer through the development of more potent and less toxic cancer therapeutics. He is developing a research program that integrates basic laboratory research, molecular characterization of clinical samples, and clinical trials of molecularly targeted cancer therapeutics. The focus of his laboratory and clinical activity is on primary brain tumors, in particular glioblastoma. Glioblastoma is the most common malignant brain tumor in adults and one of the most aggressive human cancers. His interest in this disease is based on the urgent need for new therapeutic strategies and our already substantial knowledge of mutations in the glioblastoma genome which might be targeted with specific signal transduction inhibitors. Other important disease-specific features related to human glioblastoma include: 1) the ability to closely monitor the total tumor burden by MRI (since this tumor does not metastasize), 2) repetitive access to tumor tissue due to the frequent need for salvage surgery, and 3) the ability to determine clinically meaningful treatment endpoints within a relatively short period of time (e.g., six month progression-free survival). All of these latter aspects were instrumental for the successful clinical development of BCR/ABL kinase inhibitors for leukemia and make glioblastoma a particularly appealing disease model to advance targeted therapeutics to solid cancer. Dr. Mellinghoff is a project leader of project 1.

Image of William Pao, M.D., Ph.D.

William Pao, M.D., Ph.D.
Dr. William Pao, M.D., Ph.D., is an Associate Professor of Medicine in the Division of Hematology/Oncology at Vanderbilt University in Nashville, TN. He has secondary appointments in the Departments of Cancer Biology and Pathology, is the Director of Personalized Cancer Medicine at the Vanderbilt-Ingram Cancer Center (VICC), and is the Ingram Associate Professor of Cancer Research at VICC. Prior to his appointments at Vanderbilt, he was an Assistant Member in the Human Oncology and Pathogenesis Program and an Assistant Attending Physician on the Thoracic Oncology Service, both at Memorial Sloan-Kettering Cancer Center in New York, NY. As a physician-scientist with a special interest in thoracic oncology, Dr. Pao has focused on defining clinically relevant molecular subsets of lung cancer. He has been a leader in establishing mechanisms of sensitivity and resistance to small molecules that target the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC), and his lab has identified multiple strategies to overcome acquired resistance to such drugs in lung cancer. Dr. Pao currently serves as PI on NCI K08 and R01 grants, and a project leader on an NCI P01 grant. He has served on multiple committees at AACR and ASCO regarding translational research, and has been a journal editor for PLoS Medicine, Cancer Research, and the Journal of Clinical Oncology. Dr. Pao is a project leader of project 3.

Image of Chris Sander, Ph.D.

Chris Sander, Ph.D.
Dr. Chris Sander, Ph.D., is a theoretical physicist. Currently, he is the Director of the Computational Biology Center (CBC) and the Chairman of the Sloan-Kettering Institute's Computational Biology Program. The CBC's researchers and engineers are devoted both to basic science and to the goal of developing diagnostic and therapeutic tools that help improve the lives of people affected by cancer. They often collaborate with researchers in the lab and in the clinic to translate data -- data such as the molecular profiles of cells and tissues, the billions of letters of genome sequences, and the functions and structures of key genes -- into biological insights and prediction tools. Current areas of research in the Sander group includes identification of oncogenically altered pathways from genomic and molecular profiling in cancer, algorithms for the analysis of cancer genomics data, design of combinatorial cancer therapy, drug target identification, knowledge representation of biological pathways, protein evolution, specificity in protein networks, and the function of small RNAs. Dr. Sander is a project leader of project 1 and an investigator of project 3.

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Maribel Vazquez, Ph.D.
Dr. Maribel Vazquez, Ph.D., is an Associate Professor of Biomedical Engineering at The City College of New York (CCNY) in upper Manhattan. She received a doctoral degree in Mechanical Engineering from the Massachusetts Institute of Technology (MIT) in 2001 and has been conducting research that integrates micro- and nanotechnologies with the study of cell migration. Her laboratory has focused on the study of the chemotaxis of brain tumor cells in vitro and has been supported by the Pediatric Brain Tumor Foundation, The National Cancer Institute and the National Science Foundation. She is an investigator of project 2.

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Project 1 - Developing a Mathematical Framework to Uncover the Sequence of Genetic Events during Tumor Development

Project Leaders: Ingo Mellinghoff (Memorial Sloan-Kettering Cancer Center) and Chris Sander (Memorial Sloan-Kettering Cancer Center)

The recognition of cancer as a disease caused by the accumulation of genetic alterations has motivated large-scale efforts to annotate the cancer genome for all human cancers. Of special importance are changes that occur early during malignant transformation since they may result in oncogene addiction and represent promising targets for therapeutic intervention. In this project, we will link these emerging, large cross-sectional datasets with a novel mathematical model to predict the sequence of genetic events during tumorigenesis and then apply it to genomic datasets for primary glioblastoma, predict the sequence of associated genetic events, and examine in mice how the sequence of these genetic events affects tumor formation.

Developing a Mathematical Framework to Uncover the Sequence of Genetic Events during Tumor Development

Project 2 – The Cell-of-Origin of Human Cancers

Project Leaders: Eric Holland (Memorial Sloan-Kettering Cancer Center) and Franziska Michor (Dana-Farber Cancer Institute)

Although knowledge of the target of transformation is important for an understanding of the natural history of cancers and has therapeutic implications, the cell of origin of most cancers is still unknown. In this project, we aim to design mathematical frameworks to investigate the cell of origin of Myeloproliferative Neoplasms (MPNs) as well as PDGF-driven gliomas, and validate the predictions and further refine the mathematical model with data derived from murine models of MPNs and glioma which allow for expression of the known pathogenic mutations in the appropriate stem/progenitor cell compartments. These interdisciplinary approaches will enable us to identify the cell of origin of MPN and glioma and will also have relevance to other tumor types arising in tissues that are organized as a differentiation hierarchy.

The Cell-of-Origin of Human Cancers

Project 3 – Novel Tools to Predict and Prevent the Emergence of Resistance against Targeted Drugs and Radiation Therapy

Project Leaders: William Pao (Vanderbilt University) and Franziska Michor (Dana-Farber Cancer Institute)

Since acquired resistance to either targeted or radiation therapies represent severe limitations, and since existing treatment schedules were established empirically, we propose an interdisciplinary approach utilizing mathematical modeling and unique experimental systems to predict and prevent the emergence of resistance against targeted drugs and radiation therapy. We will develop a mathematical framework for the general scenario of drug resistance emerging during therapy with targeted drugs, apply the models to minimize the risk of resistance to EGFR tyrosine kinase inhibitors in lung cancer, using quantitative measurements obtained from appropriate isogenic cell lines and in vivo transgenic lung tumor models, and apply the models to minimize the risk of resistance to radiation in medulloblastoma, using quantitative measurements obtained from a novel transgenic mouse model. Collectively, these studies are expected to lead to the rational design of clinical trials to prevent the emergence of resistance in patients treated with targeted drugs or radiation therapy.

Novel Tools to Predict and Prevent the Emergence of Resistance against Targeted Drugs and Radiation Therapy

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Core 1 - Single cell phospho-profiling core facility

Core Leader: Dr. Rong Fan

Dr. Fan anticipates developing five single cell platforms to facilitate all three projects in the DFCI PSOC. These platforms include: (1) single cell secretomic profiling, (2) single cell phospho-protein profiling, (3) single cell whole genome amplification, (4) single cell epigenome amplification and (5) high-content laser imaging cytometry.

In addition, the core will be equipped with the state-of-the-art single cell analysis tools such as flow cytometer and motorized fluorescence microscope. These platforms together will enable a suite of functional evaluation ranging from genomics, epigenomics to proteomics of single primary tumor cells and examine phenotypic variability, functional state of activation and/or the response to drugs in heterogeneous populations of cells. For example, they will provide approaches to measure phospho-profiles of drug-sensitive pathways (e.g. EGFR), downstream signaling cascades (e.g. AKT and MAPK pathways), cell-cycle phases, and apoptotic response at the single cell level. Special emphasis is given to quantification of parameters for the dynamics of tumor cell proliferation and death (e.g. during drug treatment with varying concentration). This core contributes to the PS-OC by providing quantitative measurements that parameterize "cellular fitness"(as a convolution of cell cycle and apoptosis dynamics) and signaling events in colorectal/gliomaneurospheres/leukemia lines of the relevant genotypes; these measurements are then inserted into the modeling framework of the PS-OC. To achieve these core's objectives (i.e. to establish a facility dedicated to providing quantitative measurements of cancer growth, signaling, and response to drugs in single-cell resolution for animal and cell line models of tumorigenesis), we 1) establish validated quantitative measurements of proliferation and death rates of primary tumors and associated molecular signatures; 2) provide single-cell resolution of the variability of cellular signaling response during varying conditions (such as exposure to growth factors, cytokines, drugs, radiation therapy etc); and 3) establish systematic protocols to test the drug response of primary tumor cells.

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Relevant Links

Dana-Farber Cancer Institute's internal newsletter: Inside the Institute
Dr. Franziska Michor and Dr. Rameen Beroukhim
The goal of the PS-OC is to advance the understanding of the physical principles that govern cancer initiation, progression, response to treatment, and the emergence of resistance. This article explains more about this innovative approach geared towards better understanding and controlling cancer.

Dr. Franziska Michor
Why aren't scientists using math to decipher how cancer grows and mutates? Dr. Franziska Michor applies computational biology to crack cancer's code.

Dana-Farber Cancer Institute's external newsletter: Paths of Progress
Dr. Franziska Michor
The goal of the PS-OC is to advance the understanding of the physical principles that govern cancer initiation, progression, response to treatment, and the emergence of resistance. This article explains more about this innovative approach geared towards better understanding and controlling cancer.

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