MIT/Mayo Physical Sciences Center for Drug Distribution and Drug Efficacy in Brain Tumors
List of Collaborating Institutions
Mayo Clinic, Brigham and Women’s Hospital, Dana-Farber Cancer Institute
The selection of relevant therapeutic agents with optimal pharmacokinetic and pharmacodynamic properties to adequately suppress the intended target across the entire target cell population will be central to the success of genomics-guided precision medicine strategies. Optimal drug therapy for brain tumors is especially challenging due to multiple physical barriers within the vasculature and tumor microenvironment that can result in highly heterogeneous drug delivery. This results in a significant fraction of tumor cells being exposed to sub-therapeutic drug levels that limit the efficacy of therapy and may lead to compensatory cell signaling and emergence of drug resistance. Thus, a central tenet of our Center is that failure to understand limitations in the physical delivery and distribution of novel therapeutics into brain tumors is a major reason for the collective failure to extend the exciting treatment advances and survival gains realized in peripheral malignancies to the treatment of brain tumors. In this PS-OC, we will focus on understanding physical factors that influence heterogeneous drug distribution and the resulting biology in a highly integrated analysis of patient and animal tumor models using 3-dimensional MR imaging, stimulated Raman scattering (SRS) microscopy, matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), immunohistochemistry (IHC), phosphoproteomics, proximity ligation assays (PLA), and RNAseq. Integration of these data sets across a series of drugs evaluated in multiple tumor models will elaborate critical factors that modulate distribution of these drugs and provide the platform for construction of a multi-scale model that could be used to select a targeted therapeutic with an optimal predicted drug distribution based on MRI features of an individual tumor.
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Forest M. White, Ph.D.
Prof. Forest White is the Principal Investigator (PI) of the PS-OC. Prof. White is a Professor in the Department of Biological Engineering at MIT, where he serves as co-Chair of the Biological Engineering Graduate Program. He is a member of the Koch Institute for Integrative Cancer Research and the Center for Environmental Health Sciences at MIT. Prof. White received his Ph.D. from Florida State University in 1997 and was a post-doctoral associate at the University of Virginia from 1997-1999. After completion of his post-doc, he joined MDS Proteomics as a Senior Research Scientist and developed phosphoproteomics capabilities for the company. In July 2003 he joined the Department of Biological Engineering at MIT as an Assistant Professor; in 2007 he was promoted to Associate Professor, and in 2014 he was promoted to Full Professor. Prof. White’s laboratory investigates cellular signaling mechanisms in cancer, metabolic diseases, and immunology.
Jann Sarkaria, M.D.
Jann Sarkaria, MD is a physician-scientist and Professor of Radiation Oncology at the Mayo Clinic in Rochester, Minnesota. His clinical focus is treating lung and brain malignancies with external beam photon or proton radiation. His laboratory work focuses on developing novel therapeutic strategies for treating both primary and metastatic brain tumors. Central to this work is the development and characterization of a large panel of patient-derived xenografts (PDXs) developed from brain tumor resection specimens. His laboratory has used these PDX models extensively to evaluate the efficacy of conventional and molecularly targeted therapies for glioblastoma (GBM). Central research themes include evaluation of genetic and epigenetic mechanisms of therapy resistance to radiation and temozolomide, development of novel radio- or chemo-sensitizing agents for brain tumors, and understanding the influence of heterogeneous drug delivery into brain tumors on treatment response and evolution of therapy resistance. All of these themes are highly translational with an ultimate goal of improving therapy for brain tumors.
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K. Dane Wittrup, Ph.D.
Protein engineers can engineer antibodies and scaffold proteins with widely varying size and affinity, however the field has lacked any design principles for how best to exploit this capability. We developed simple scaling analyses that illustrated the tradeoffs between fundamental rate processes (clearance, extravasation, endocytosis) and have successfully predicted all subsequent experimental exploration of the effects of varying size and affinity on tumor uptake. We and others continue to use these models to design new drug candidates and examine their pharmacokinetics.
Douglas A. Lauffenburger, Ph.D.
Douglas A. Lauffenburger is Ford Professor of Bioengineering and (founding) Head of the Department of Biological Engineering at MIT. Professor Lauffenburger also holds appointments in the Department of Biology and the Department of Chemical Engineering, is a member of the Center for Biomedical Engineering, Center for Environmental Health Sciences, Center for Gynepathology Research, and Koch Institute for Integrative Cancer Research. A central focus of his research program is in receptor-mediated cell communication and intracellular signal transduction important in pathophysiology with application to drug discovery and development, with emphasis on development of predictive computational models derived from quantitative experimental studies. More than 100 doctoral students and postdoctoral associates have undertaken research education under his supervision, and he has served as a consultant or scientific advisory board member for a number of bio/pharma companies including Applied BioMath, Array BioPharm, Astra-Zeneca, Complete Genomics, Entelos, Genentech, Immuneering, Merrimack Pharmaceuticals, Nodality, Pfizer, and Torque Therapeutics.
Nathalie Y.R. Agar, Ph.D.
Nathalie Y.R. Agar, Ph.D. is the founding Director of the Surgical Molecular Imaging Laboratory (SMIL) in the Department of Neurosurgery at Brigham and Women’s Hospital, and Associate Professor of Neurosurgery and of Radiology at Harvard Medical School. Dr. Agar’s multidisciplinary training includes a B.Sc. in Biochemistry, Ph.D. in Chemistry, and postdoctoral fellowships in Neurosurgery at McGill University, and BWH/HMS. Her research aims to implement comprehensive molecular diagnoses through improved biochemical classification, enabling surgeons and oncologists to tailor treatment from the time of surgery. Her laboratory focuses on the study of targeted therapeutics for brain cancer from pre-clinical animal models to clinical trials’ samples, considering their ability to access the central nervous system. Toward this end, her group uses a range of imaging and analytical technologies such as 3D MALDI FTICR mass spectrometry imaging, LESA mass spectrometry, stimulated Raman scattering, bright field and fluorescence microscopy, and specialized data and image analyses.
William F. Elmquist, PharmD, Ph.D.
William F. Elmquist is currently Professor and Director of the Brain Barriers Research Center, at the University of Minnesota, Department of Pharmaceutics. He received his pharmacy degree at the University of Florida, and Pharm.D. and Ph.D. (pharmacokinetics) from the University of Minnesota. His research has studied the influence of active efflux transporters in the blood-brain barrier (BBB) on CNS drug distribution. An important project currently underway is examining the determinants of anticancer drug permeability in the blood-brain barrier to improve the treatment of brain tumors. Long-term objectives of Dr. Elmquist's research include examining expression and regulation of transport systems in key tissues that influence drug disposition, and how variability in expression, either genetically or environmentally controlled, may contribute to variability in drug response in the patient. Dr. Elmquist has long been a consultant to the pharmaceutical industry and the NIH, served on many journal editorial boards, and is a Fellow of the American Association of Pharmaceutical Scientists (AAPS).
Nhan L. Tran
Dr. Nhan L. Tran is a Professor in the Department of Research and Cancer Biology at Mayo Clinic Arizona. Dr. Tran’s research has been focused on determining the cellular and biochemical mechanisms of action of candidate genes expressed in highly invasive glioblastoma cells and their matrix of aberrant signaling to discover points of convergence that can serve as targets of vulnerability for therapeutic intervention. His laboratory focuses on the identification and characterization of certain members of the super family of cytokine receptors, the tumor necrosis factor receptors (TNFR) and their downstream signals via RhoGTPases to play important roles in modulating glioblastoma cell adhesion, invasion and cell survival. In addition, Dr. Tran’s expertise also lies in high-throughput assay development, and applying molecular chemical libraries screens to exploit novel GBM targets as an innovative strategies to treat invasive glioblastoma. In addition, his research also focuses in characterizing GBM intratumor heterogeneity and genomic aberration of invasive glioblastoma cells by implementing range of genomic technologies (whole genome, exome, RNA sequencing and methylation) to study therapeutic resistance and drug delivery.
Leland S. Hu, M.D.
Dr. Hu is an Assistant Professor in Radiology at the Mayo Clinic College of Medicine and serves as an attending Neuroradiologist at Mayo Clinic in Phoenix, Arizona. He received his medical degree at the University of Texas – Southwestern Medical School, where he also completed his medical internship and residency training in Diagnostic Radiology. After completing his two-year clinical fellowship in Diagnostic Neuroradiology at Barrow Neurological Institute, he joined the medical faculty at Mayo Clinic in 2008. Dr. Hu’s research focuses on the development and implementation of advanced imaging methods to improve diagnosis, treatment planning, and treatment monitoring in brain tumors. His initial work has sought to improve the accuracy of surveillance imaging in glioma, and his group published one of the first studies that validated the accuracy of Dynamic Susceptibility-weighted Contrast-enhanced (DSC) perfusion MRI (pMRI) to distinguish high-grade glioma recurrence from post-treatment radiation effects (e.g., pseudoprogression, radiation necrosis). He and his group have utilized image-guide tissue analysis and stereotactic coregistration to help overcome the challenges of intratumoral heterogeneity. Dr. Hu has recently published studies that have developed MRI and texture-based biomarkers of regional tumor cell invasion and intratumoral genetic heterogeneity in glioblastoma. Dr. Hu currently serves on the Imaging Committee for the Alliance for Clinical Trials in Oncology and is an Associate Member of the NIH Quantitative Imaging Network (QIN).
Daniel J. Ma, M.D.
Daniel J. Ma is currently an Assistant Professor of Radiation Oncology at the Mayo Clinic in Rochester, MN. He received his M.D. from the Washington University School of Medicine in St. Louis, MO and did residency training at the Mallinckrodt Institute of Radiology. His research is centered on using next-generation sequencing (NGS) techniques to predict treatment response in glioblastoma multiforme (GBM) and using circulating tumor DNA (ctDNA) to detect early treatment failure. Dr. Ma serves on the Radiation Oncology Research Executive Committee at Mayo Clinic.
Ian F. Parney M.D., Ph.D
Dr. Parney is Associate Professor and Vice-Chair (Research) of the Department of Neurosurgery at Mayo Clinic Rochester where he is also a member of the Department of Immunology and the Neuro-Oncology Program of the Mayo Clinic Cancer Center. He received his MD and PhD degrees and completed his neurosurgical training at the University of Alberta and completed further subspecialty and post-doctoral training in the Dept. of Neurosurgery at the University of California San Francisco. Dr. Parney’s clinical efforts are focused on malignant brain tumor surgery. His laboratory focuses on malignant glioma immunology and immunotherapy. He is a principal investigator on multiple local and national glioma immunotherapy clinical trials.
Kristin Swanson M.D. Ph.D
Dr. Swanson received her BS in Mathematics in 1996 from Tulane University followed by her MS (1998) and PhD (1999) in Mathematical Biology from the University of Washington. Following a postdoctoral fellowship in Mathematical Medicine at UCSF, she joined the faculty at the University of Washington in 2000, with appointments in both Neuropathology and Applied Mathematics. In 2015, she joined Mayo Clinic in Arizona as Professor and Vice Chair of the department of Neurological Surgery. She also holds appointments at Arizona State University and the Translational Genomics Institute.
Dr. Swanson’s research lab has served to pioneer the burgeoning field of mathematical neuro-oncology generating compelling data to support the practical application of patient-specific bio-mathematical models of glioma to assess, predict and optimize treatment. Her research efforts have been supported through funding by the NIH, numerous foundations, the James D. Murray Endowed Chair at the University of Washington, TGen and the Mayo Clinic.
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Project 1: Modeling the Interface between Non-invasive Imaging and Drug Distribution
The goal of this project is to develop and validate a “minimal” model that will capture intra- and inter-tumor heterogeneity to predict clinically relevant levels of drug distribution using routine imaging. In this project, we will use a combination of patient data, GBM patient-derived xenografts (PDXs), matrix-assisted laser desorption/ionization mass spectroscopy imaging (MALDI-MSI), and stimulated raman spectroscopy (SRS) to quantify the differences in drug distribution within and across tumors and, in doing so, develop a computational framework for predicting the efficacy of BBB-penetrant and BBB-impenetrant drugs for the treatment of GBMs.
Project 2: Defining the relationship between tumor composition, spatial heterogeneity, drug delivery, and drug efficacy
The ultimate goal of this project is to determine the physical factors regulating therapeutic distribution and therapeutic efficacy in brain tumors. To this end, we have developed a highly innovative integrated strategy to quantitatively map therapeutic distribution with spatially registered characterization of the tumor architecture and therapeutic efficacy, all within a given tumor specimen. Specifically, in this approach we will combine MALDI-MSI to quantify drug distribution, stimulated Raman scattering imaging for label free analysis of tumor architecture with optical imaging resolution, immunohistochemistry to determine the tumor cell state and target distribution, proximity ligation assays for cellular spatial resolution of signaling response to therapy, and laser-capture microdissection RNASeq to quantify spatially resolved transcriptional response to therapy. All of these approaches will be performed in serial sections from individual tumors, thereby enabling the integration of spatially registered data. Together with mass spectrometry based phosphoproteomics and RNASeq analysis to quantify the dynamic signaling and transcriptional network response to a spectrum of defined drug concentrations in additional tumor specimens, the data generated in this project will (1) map spatially heterogeneous drug distribution and drug efficacy and (2) enable the computational modeling of the physical factors governing distribution and regulating the cellular and molecular response to different local drug concentrations.
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Animal and Pharmacology Core
The studies in this PS-OC will focus on evaluating a spectrum of EGFR- and RAF-targeted therapies in animal tumor models of glioblastoma (GBM) and melanoma brain metastases, and the Animal and Pharmacology Core will provide critical infrastructure for these studies. The Core will be led by Dr. Jann Sarkaria, who has extensive expertise in animal tumor models and by his long-time collaborator, Dr. William Elmquist, who is an expert in pharmacokinetic modeling of drug delivery into the brain. The main function of the Core will be to manage all aspects of the experiments that involve live animals and, in collaboration with the Administrative Core, to manage distribution of biospecimens and imaging data to the appropriate investigators. The Core will manage some experiments that are performed expressly for an individual project and others where the analysis of imaging and biospecimens will bridge both projects. The Core will have access to the extensive Mayo PDX xenograft collection in collaboration with the Mayo SPORE in Brain Cancer Animal Core.
Data Handling and Integration Core
The Data Handling and Integration Core will provide key infrastructure to each Project through data management and storage, integration of diverse data types, and model construction. The Core will be led by Dr. Douglas Lauffenburger, an expert in systems biology and application of engineering principles to biological systems, with over twenty years of expertise in developing computational modeling techniques and applying these approaches to extract key biological insights from complex systems. Other members of the core include Dr. K. Dane Wittrup, an expert in protein engineering and quantitative pharmacology, Dr. Kristin Swanson, an expert in computational modeling with strong experience in extracting biological insight from non-invasive imaging techniques, and Dr. Nathalie Agar, an expert in MALDI-MSI, stimulated Raman spectroscopy, and imaging of drug distribution in brain tumors. Together, these investigators provide the requisite expertise and experience to fulfill each of the Core functions.
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Education and Outreach Activities
Education and Outreach activities in the MIT/Mayo PSOC occur at a variety of levels. At the undergraduate level, we focus on cross-disciplinary training of undergraduates in each of the labs associated with our center, such that students get exposed to principles of physical science, engineering, and molecular biology within the context of an aspect of one of the projects in our center. At the graduate and post-doctoral level, we focus on inter-lab cross-disciplinary training, with students from each lab within the center traveling to other labs to improve their knowledge of different techniques and perspectives, with the goal of developing trainees that are fluent in physical sciences, engineering, and oncology. Finally, at all levels, including trainees, PIs, and staff, we aim to inform as to the role of the blood-brain barrier in limiting drug distribution and therefore drug efficacy in brain tumors, while also providing information on tumor heterogeneity and adaptive response to therapy. To this end, we have hosted numerous speakers at each institution, and organized 2 symposia thus far, including a mini-symposium on the role of the BBB in GBM therapy, and a jointly organized 2-day PSOC/SPORE workshop on brain tumors. We are in the process of co-organizing (with the University of Minnesota PSOC) the next Brain Tumor Symposium to be held in Minneapolis in May. Finally, several investigators from our PSOC have presented talks at a range of conferences and symposia, including multiple presentations at the Anticancer Drug Discovery and Development Conference at the recent Society for NeuroOncology meeting.
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