Dana-Farber Cancer Institute Physical Sciences-Oncology Center
Dana-Farber Cancer Institute, Boston, MA
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.
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)
Show/Hide Details
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.
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)
Show/Hide Details
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.
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)
Show/Hide Details
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.
Core 1 - Single cell phospho-profiling core facility
Core Leader: Gregoire Altan-Bonnet (Memorial Sloan-Kettering Cancer Center)
The Single-Cell Profiling Core performs quantitative single-cell assays and addresses the need for new technologies that enable the monitoring of the functional response of primary tumor cells in their native context. To achieve this, we rely on recent developments in flow cytometry that multiplex measurements of phenotypic variability, functional state of activation and/or the response to drugs in heterogeneous populations of cells. Specifically, this core focuses on measuring 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 with special emphasis on the quantification of parameters for the dynamics of tumor cell proliferation and death (e.g. during drug treatment with varying concentration).
Franziska Michor, Ph.D.
Franziska Michor, PhD, 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.
Eric C. Holland, M.D., Ph.D.
Eric Holland, MD, PhD, has been on the faculty at Memorial Sloan-Kettering Cancer Center (MSKCC) since December of 2000. He is currently an Attending Surgeon in the Department of Neurosurgery, an Attending in the Department of Neurology, and a Member of Sloan Kettering Institute’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 Bran Tumor Center, 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. Dr. Holland’s laboratory focuses primarily on the understanding of the molecular mechanisms underlying the pathogenesis of central nervous system 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.
