The Methodist Hospital Research Institute Physical Sciences-Oncology Center evaluates the process of mass transport in cancer to generate novel methods to improve diagnosis and treatment of cancer. This center focuses on hepatic, breast, colorectal, and pancreatic primary cancers as well on liver metastasis of the last three conditions. The investigators show that transport differentials are very important in the ability to efficiently treat malignancies. Mathematics, innovative engineered transport probes and state-of-the-art imaging are integrated to elucidate the transport physics across various physical and biological barriers related to tumorigenesis and drug delivery. Notably, this trans-disciplinary team studies the physical barriers to the evolution of liver metastasis and the administration of novel carriers to surpass these barriers. Genetic signatures which encode to mass transport variables are also being evaluated based on animal models and clinical cases. Ultimately, these studies will provide a clearer grasp of the origin, function and physics of biological barriers, and in turn will accelerate basic discovery and assist in the design for potential therapeutics.
Principal Investigator: Mauro Ferrari, Ph.D.
Senior Scientific Investigator: Steven A. Curley, M.D.
Collaborators: Harvard Medical School, Massachusetts General Hospital, University of Texas-Austin, U.T. M.D. Anderson Cancer Center, William Marsh Rice University
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Mauro Ferrari, Ph.D., Principal Investigator
Dr. Mauro Ferrari serves as President and CEO of The Methodist Hospital Research Institute and holds the Ernest Cockrell Jr. Distinguished Endowed Chair. He is also professor of biomedical engineering medicine at Weill Cornell Medical College, president of the Alliance for NanoHealth in Houston, and holds professorships at the University of Texas Health Science Center at Houston, the University of Texas MD Anderson Cancer Center Graduate School of Biomedical Sciences, Rice University, The Tecnologico de Monterrey School of Medicine and Health Sciences in Monterrey, Mexico, and the University of Naples "Federico II" in Naples, Italy.
Dr. Ferrari is a founder of biomedical nano/microtechnology, especially in their applications to drug delivery, cell transplantation, implantable bioreactors, and other innovative therapeutic modalities. He has published more than 200 peer reviewed journal articles and books and has invented more than 30 issued patents. His contributions have been recognized with a variety of accolades, such as the Presidential Young Investigator Award of the National Science Foundation and the Shannon Directors Award of the National Institutes of Health. Dr. Ferrari began his academic career at the University of California, Berkeley, where he tenured in material science, civil engineering, and bioengineering. Upon recruitment to the Ohio State University, he served as the Edgar Hendrickson Professor of Biomedical Engineering and held numerous other positions in the fields of internal medicine, mechanical engineering, materials science, and health sciences technology and commercialization. He was also associate director of the Dorothy M. Davis Heart and Lung Research Institute and director of the Biomedical Engineering Center. Dr. Ferrari also served as Special Expert on Nanotechnology at the National Cancer Institute from 2003 to 2005, providing leadership into the formulation, refinement, and approval of the NCI's Alliance for Nanotechnology in Cancer, currently the world's largest program in medical nanotechnology.
Steven A. Curley, M.D., Senior Scientific Investigator
Steven A. Curley, M.D., F.A.C.S. is Professor of Surgery, Chief of Gastrointestinal Tumor Surgery, and Program Director of Multidisciplinary Gastrointestinal Cancer Care at M. D. Anderson.
The current focus of his basic science research program is use of a novel non-invasive radiofrequency field generator combined with cell-associated nanoparticles that release heat in response to the radiofrequency field to treat malignant tumors. Ongoing studies involve adding tumor-directed targeting molecules to the nanoparticles to enhance uptake by malignant cells while minimizing uptake by normal cells.
Dr. Curley earned his medical degree from the University of Texas Medical School at Houston. He completed a general surgery residency at the University of New Mexico Hospitals, and then completed a fellowship in Surgical Oncology at the University of Texas M. D. Anderson Cancer Center (MDACC). He has been on the faculty in the Department of Surgical Oncology at MDACC since completing his fellowship.
His clinical practice and research focuses on surgical and new treatments for patients with primary or metastatic liver tumors. He has been a pioneer in designing new treatments for patients with liver tumors, including radiofrequency ablation, improved techniques for surgical removal of liver cancers, and several types of direct tumor injection therapy.
Dr. Curley is principal investigator on a number of protocols at MDACC involving radiofrequency ablation of liver tumors or use of novel therapies to treat hepatocellular cancer or colorectal cancer liver metastases. He is also principal investigator on an international protocol involved in screening high-risk hepatitis virus patients for hepatocellular cancer and then using surgical therapy, radiofrequency ablation, or other direct injection treatments to treat patients diagnosed with small hepatocellular cancers.
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Biana Godin Vilentchouk, Ph.D., M.Sc.Pharm., Project 1 Co-Leader
Dr. Biana Godin Vilentchouk earned her Ph.D. in Pharmaceutical Sciences from the Hebrew University of Jerusalem in 2006. During her PhD studies, Dr. Godin Vilentchouk focused on designing a non-invasive treatment for the hard-to-treat skin deep infections and on nasal delivery of proteins. She was recruited as a Postdoctoral trainee in the field of Cancer Nanotechnology to the research team of Dr. Mauro Ferrari at the University of Texas Health Sciences Center. Her postdoctoral research focused on injectable multistage nanovectors (MSVs) for cancer treatment and imaging. Her work provided insightful understanding of the interactions of MSVs with immune cells in vivo and in vitro, biocompatibility of MSV, effect of geometry and targeting moieties on MSV biodistribution, and evaluation of MSV systems as near-infra red and MRI imaging agents. During the three years of her postdoctoral research, Dr. Godin Vilentchouk published numerous book chapters, and peer-reviewed articles and reviews in top journals including Nature Nanotechnology and Cancer Research. She also received awards for her work at international conferences. In October 2010, Dr. Biana Godin Vilentchouk joined the Department of Nanomedicine at TMHRI.
Renata Pasqualini, Ph.D., Project 2
Dr. Pasqualini is the Buchanan & Seeger Professor of Medicine and Experimental Diagnostic Imaging at The University of Texas M. D. Anderson Cancer Center. She received her Ph.D. degree in Biochemistry from the Ludwig Institute for Cancer Research at the University of São Paulo and her postdoctoral training from The Children's Hospital Medical Center of Harvard Medical School, Dana-Farber Cancer Institute, and the Burnham Institute in La Jolla. Dr. Pasqualini is an internationally recognized expert in vascular biology, metastasis and angiogenesis. She originally co-developed the in vivo phage display targeting system and is well known for her contributions towards identifying organ- and tumor-specific ligands to target vascular receptors. Dr. Pasqualini has a close scientific collaboration with Dr. Arap, with whom she directs a laboratory with graduate students, postdoctoral and medical oncology fellows, and staff at M. D. Anderson Cancer Center. She serves and chairs grant review boards for NIH programs (NCI, NIDDK, RAID, SBIR, STTR), for the U.S. Departments of Defense (Breast and Prostate Cancer Research Program) and the Department of Energy, in addition to several international funding agencies. Dr. Pasqualini has been working with all aspects of phage display technology for nearly 15 years and along with Dr. Arap has published over 140 original peer-reviewed research manuscripts.
Lon J. Wilson, Ph.D., Project 2
Lon J. Wilson has been a Professor of Chemistry at Rice University for almost 40 years. He has held NSF and NIH-sponsored fellowships and has published over 175 manuscripts and book chapters. Professor Wilson's research program involves bringing carbon nanotechnology to the fields of biology and medicine. The nanoparticle "building blocks" of this program are fullerenes (C60), endohedral metallofullerenes (M@C60), and ultra-short single-walled carbon nanotube capsules (US-tubes). Externally, these carbon nanostructures are being chemically derivatized to make them biocompatible and cell-specific through peptide and antibody targeting. Internally, the nanostructures are being loaded with materials of medical interest for diagnostic and therapeutic medicine. Materials of interest include Fe2O3 and Gd3+ ions for MRI, I2 for X-ray CT and alpha-radionuclides (At-211) for alpha-radiotherapy against cancer. Nanoengineered materials promise great advances in medicine, and, working with colleagues at various medical centers, Wilson's goal is to bring key, high-performance materials to the clinic as soon as possible.
Haifa Shen, M.D., Ph.D., Project 3 Leader
Dr. Shen earned his M.D. from Zhejiang University Medical School of Hangzhou, China in 1985, and his Ph. D. from the University of Texas at Houston in 1997. After completing a four-year postdoctoral fellowship at the National Cancer Institute, he worked on drug development at Lexicon Pharmaceuticals. He returned to the University of Texas at Houston Medical School as an assistant professor before becoming a member of The Methodist Hospital Research Institute in 2010.
Neal G. Copeland, Ph.D., Project 3
Neal Copeland received his Ph.D. in Biochemistry from the University of Utah. Following postdoctoral studies at Harvard Medical School, he joined the staff of The Jackson Laboratory and then the National Cancer Institute-Frederick, where he was Director of the Mammalian Genetics Laboratory, the forerunner of the Mouse Cancer Genetics Program that he also directed. He moved to the Institute of Molecular and Cell Biology in Singapore in 2006, where he served as the Executive Director for most of his stay. In 2011 he returned to the US to serve as Director of the The Methodist Cancer Biology Program at The Methodist Hospital Research Institute. For more than 30 years he has co-headed a laboratory with Nancy Jenkins. The focus of their current research is cancer genetics. They have co-authored more than 780 papers and are among the 50 most cited biomedical research scientists in the world today. Both have served on numerous scientific advisory and editorial boards and they have consulted for several biotechnology and pharmaceutical companies. Both are also members of the US National Academy of Sciences.
Nancy A. Jenkins, Ph.D., Project 3
Dr. Nancy Jenkins received her Ph.D. in molecular and cellular biology from Indiana University. Following postdoctoral studies at Harvard Medical School she joined the staff of The Jackson Laboratory and then the National Cancer Institute-Frederick, where she was a Senior Investigator and Head of the Molecular Genetics of Development Section for 22 years. She moved to the Institute of Molecular and Cell Biology in Singapore in 2006, where she served as Deputy Director for most of her stay. In 2011 she returned to the US to serve as Co-Director of The Methodist Cancer Biology Program at The Methodist Hospital Research Institute. For more than 30 years she has co-headed a laboratory with Neal Copeland; the focus of their current research is cancer genetics. They have co-authored more than 780 papers and are among the 50 most cited biomedical research scientists in the world today. Both have served on numerous scientific advisory and editorial boards and they have consulted for several biotechnology and pharmaceutical companies. Both are also members of the US National Academy of Sciences.
Vittorio Cristini, Ph.D., Core 1 Co-Leader
Vittorio Cristini, PhD, joined the University of New Mexico in 2010. He is the Victor & Ruby Hansen Surface Professor of Molecular Modeling of Cancer in the UNM Cancer Center, and Professor with Tenure of Pathology, Chemical and Biomedical Engineering at UNM. He is a leading expert and researcher in the fields of mathematical and computational biology, applied and computational mathematics, physical oncology, complex fluids and microfluidics, and multidisciplinary (bio)materials science. He serves as editor for Cancer Research and several biomedical journals, and has published one book monograph with Cambridge University Press, numerous book chapters, and over 70 journal articles. Among a number of awards, Dr. Cristini was the first recipient of the "Andreas Acrivos Dissertation Award in Fluid Dynamics" by the American Physical Society in 2000. His 2005 paper in the Bulletin of Mathematical Biology was in the top 0.1% of citations in the field of Mathematics and has been designated as a "New Hot Paper in the field of Mathematics" by the ISI Web of Knowledge; in addition, two articles have been featured in the Cancer Research Highlights of the American Association for Cancer Research.
Dr. Cristini's research has been highly recognized internationally and by the media and several science museums in the US. He has been supported by the Cullen Trust for Health Care, the National Science Foundation, the National Cancer Institute, the Department of Defense, the State of California, and the State of Texas, among others. Currently, Dr. Cristini serves as overall PI, Project PI, and Core PI on several NSF, NIH, and DoD grants focused on the development of predictive, multi-scale, patient-specific computational models of tumor growth and response to treatment, most notably as part of two NCI Physical Sciences in Oncology Centers (PS-OC), one NCI Center for Excellence in Cancer Nanotechnology (CCNE), and one NCI Integrative Cancer Biology Program (ICBP) center grant. At UNM, he has developed and taught a novel course on Computational Biomedicine, and is currently mentoring and training graduate students, postdocs, and research assistant professors, including STMC and ASERT IRACDA mentees. Dr. Cristini has been appointed as Senior Scientist Fellow of The Methodist Hospital Research Institute, Houston, as SULSA professor by the Scottish Universities Life Sciences Alliance, and as Honorary Professor of Mathematics by the University of Dundee, Scotland.
Paolo Decuzzi, Ph.D., Core 1 Co-Leader
Dr. Decuzzi earned his M.Sc. degree in Mechanical Engineering from the Politecnico di Bari, one of the three Politecnical Schools in Italy, and his Ph.D. degree in Mechanical Engineering from the University of Naples - Federico II. His Ph.D. course was developed in collaboration with the Department of Theoretical and Applied Mechanics at the University of Michigan - Ann Arbor, where he worked on the multiscale modeling of adhesion and friction as a visiting scientist. He became Assistant Professor of Mechanical Engineering at the Politecnico di Bari (IT) in 2003, and Associate Professor of Biomedical and Mechanical Engineering at the School of Medicine of the University of Magna Graecia (IT) in 2005. In the same year, he co-founded the Center of BioNanotechnology and Engineering for Medicine, one of the first Nanotechnology/NanoEngineering laboratories established in a medical school. In 2007, he moved to The University of Texas Health Science Center Houston as an Associate Professor. In 2010, Paolo Decuzzi joined The Methodist Hospital Research Institute.
Seok-Hyun (Andy) Yun, Ph.D., Core 2 Co-Leader
Dr. Yun received his Ph.D. degree in physics from KAIST, Korea, in 1997. He was a Chevening Scholar in 1996 and a visiting graduate student in Optoelectronics Research Centre at University of Southampton, UK. His thesis research in fiber optics has led to a $68M-funded startup company, Novera Optics, Inc., in San Jose, CA. In 1999-2003, he worked for this company, which was later acquired by LG-Nortel, as a founding member and engineering manager. In 2003, moving his career from industry to academia and from optical telecommunications to biomedical optics, he joined the Wellman Center for Photomedicine at Massachusetts General Hospital and Harvard Medical School. Currently, he also holds an affiliated faculty position in the Harvard-MIT Division of Health Sciences and Technology and a visiting professorship at KAIST. The broad goal of Dr. Yun's research is to develop optical techniques and to apply them to significant biomedical problems. His research spans an entire spectrum from invention and innovation to biological sciences and clinical translation. His research activities involve close collaborations with academic partners across many disciplines including gastroenterology, immunology, laryngology, oncology, ophthalmology, surgery and transplantation, as well as physics, mechanics, and bio and nano materials.
Anne L. van de Ven, Ph.D., Core 2 Co-Leader
Dr. Anne van de Ven is a postdoctoral researcher at The Methodist Hospital Research Institute in Houston, Texas, where she leads the development of optical techniques for monitoring nanoparticle-based drug delivery and tissue response to treatment. She received her Ph.D. in Bioengineering from the laboratory of Dr. Rebecca Richards-Kortum at Rice University in 2008. Her thesis research involved the delivery of molecular-specific optical contrast agents for cancer biomarker detection in live cells and tissues. From 2009 to present, she has trained under the supervision of Dr. Mauro Ferrari and Dr. Paolo Decuzzi. Dr. van de Ven has nine years experience in translational research, clinical collaboration, and pre-clinical experimental design. Her areas of expertise include: intravital imaging, optical instrumentation, bio-nanoparticle design and characterization, drug delivery, and proteomics. She actively serves as key personnel in four multi-institutional grants and leads collaborations across academia, government institutions, and hospitals.
Kenji Yokoi, M.D., Ph.D., Core 3 Leader
Dr. Yokoi received his M.D. degree in 1992 and Ph.D. degree in 1997 from the Kanazawa University, School of Medicine and Graduate School of Medicine respectively. Dr. Yokoi completed his postgraduate research fellowship at the University of Texas MD Anderson Cancer Center in Houston, TX. He then accepted a position as an instructor in the Department of Cancer Biology at MD Anderson and as an instructor of general and cardiothoracic surgery for Kanazawa University Hospital in Japan.
He was appointed to the position of assistant professor in the department of cancer biology at MD Anderson in 2007 and then as an assistant member in the department of Nanomedicine in The Methodist Hospital Research Institute in 2011. Dr. Yokoi has also held the position of visiting scientist in the department of cancer biology at MD Anderson since 2011 and guest researcher for the Cancer Research Institute of Kanazawa University since 2008−present.
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Project 1 – Directed transport physics and multi-scale therapy of colon cancer liver metastasis
Project Leaders: Mauro Ferrari, Kenji Yokoi, and Biana Godin Vilentchouk (The Methodist Hospital Research Institute), Isaiah Fidler (U.T. M.D. Anderson Cancer Center), and Renata Pasqualini (U.T. M.D. Anderson Cancer Center)
The overall goal of PROJECT 1 is to develop a broader understanding of the physical barriers and biological factors involved in the progression of liver metastasis in orthotopic models and to design novel biocompatible delivery carriers able to overcome or take an advantage of these barriers with favorable pharmacokinetics and tissue distribution profiles for highly efficient delivery of novel therapeutic and imaging agents. A physics and biology driven and mathematics-based design of the engineered drug delivery vectors will multiply the probability of recognition of the novel targets providing a synergistic solution for imaging and therapy of liver metastasis on the interface of physics, engineering, mathematics and cancer biology.
Project 1: Directed transport physics and multi-scale therapy of colon cancer liver metastasis (Ferrari/Fidler): Targeting of multistage carrier to (A) endothelial vessel walls through specific ligands; (B) to phagocytic cells of the liver (Kupffer cells) that preferentially localize to metastatic loci. One of the therapy methods to be investigated includes thermal RF ablation.
Project 2 – Non-invasive radio-frequency field induced thermal destruction of malignant cells in human hepatocellular cancer
Project Leaders: Steven Curley, Renata Pasqualini (U.T. M.D. Anderson Cancer Center), and Lon Wilson (William Marsh Rice University)
PROJECT 2 explores issues related to the progression kinetics of a primary hepatic and pancreatic tumors, developing a broader understanding of the biophysical barriers involved in the Radio Frequency (RF) based thermal therapy and MRI/CT imaging of HCC employing gold nanoparticles (AuNPs) and fullerene particles (nano-C60) (Figure 2). These include the transport of the nanoparticles towards the lesion; the sufficient and specific accumulation of the nanoparticles within the tumor cells; the heat generation upon RF activation and the heat transfer to the surrounding tissue. This goal is achieved through an integrated process where in-vitro testing and in-vivo studies are combined with predictive in-silico mathematical models.
Project 2: Non-invasive radio-frequency field induced thermal destruction of malignant cells in human hepatocellular cancer (Curley/Wilson). Targeted AuNps and nano-C60 for thermal RF ablation and imaging hepatocellular.
Project 3 – Genomic Correlates of Mass Transport Differentials
Project Leader: Neal Copeland, Nancy Jenkins, and Haifa Shen (The Methodist Hospital Research Institute)
PROJECT 3 explores the heterogeneity in transport barriers of pancreatic cancer as a direct result of multiple genetic aberrations seen in the disease. Furthermore, the effect of these most relevant genes/pathways on the transport phenotype is dependent on the specific stage of tumor development (i.e., localized, locally advanced, and metastatic), with the most pronounced transport differentials anticipated to occur at early stages of tumor development. The transport phenotype offers a mechanistic explanation for the clinical observations associated with prognostic genomic biomarkers and that this physical sciences-driven analysis will help identify novel biomarkers. Moreover, the analysis provide the basis for the rational design of innovative therapeutic strategies. Herein, we aim to characterize the transport phenotype as part of a broader approach for personalized medicine: the biophysical marker.
Project 3: Study of the biophysical mechanisms regulating the efficacy of orally administered anti-cancer therapeutics from engineered nanocarriers (Peppas); Engineered rationally designed nanoparticles avoid pH gradients and enhance the transport of chemotherapeutic drug across tight junctions in GI epithelium.
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Core 1 - BioSimulation Core
Core Leaders: Vittorrio Cristini (The University of New Mexico) and Paolo Decuzzi (The Methodist Hospital Research Institute)
The core provides mathematical tools to model and predict the behavior of small molecules and nano-sized particulate systems in terms of (i) transport dynamics within the authentic patient-specific vasculature accounting for the specific/non-specific adhesive interactions with the vascular endothelium and for the permeability of the vessel walls to both plasma and blood-borne agents; (ii) extravasation from the vascular compartment to the extravascular matrix through active (transcytosis) and passive (intravascular gaps) mechanisms; (iii) transport across the extravascular matrix and distribution within the tumor microenvironment; (iv) control of the tumor growth and angiogenic response; and (v) heat generation through remote RF/NIR activation with modeling of thermal cell damage and apoptosis.
Core 2 - Advanced Intravital Microscopy Core
Core Leaders: Seok-Hyun Yun (Harvard University/Mass General Hospital) and Anne van de Ven (The Methodist Hospital Research Institute)
The broad goals of the Advanced Intravital Microscopy Core are to provide a number of unique advanced optical systems; to collaborate with the project investigators in the design, execution, and analysis of animal experiments; and to develop new instrumentation and methodology as needs arise. We have set up an operational microscopy core with protocols for in vivo tracking of nanoparticles in various organs; developed a low-cost, battery powered multi-modal imaging devices which can be used to track the transport of optically active agents throughout 3D tissue; improve spatial resolution.
Core 3 - Orthotopic Tumor Models Core
Core Leaders: Kenji Yokoi and Biana Godin Vilentchouk (The Methodist Hospital Research Institute)
The overall goal of the Orthotopic Tumor Models Core is to provide various orthotopic mouse models for the Projects and Cores. We have established mouse models of liver metastasis in the colon cancer (KM12SM, human colon cancer; CT26, murine colon cancer), lung cancer (3LL, murine lung cancer ; PC14, human lung cancer), breast cancer ( 4T1, murine breast cancer), pancreatic cancer (L3.6pl human pancreatic cancer) and melanoma (K1735 and B16 , murine melanoma).
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CTO Workshop: Intravital Microscopy Nanoparticle Dynamics in Real-time
Real-time Intravital Microscopy for Optimization of Nanotherapeutics Delivery to Tumors
Presented by Anne L. van de Ven, Ph.D.
Biana Godin et al (2012)
Discoidal Porous Silicon Particles: Fabrication and Biodistribution in Breast Cancer Bearing Mice, Advanced Functional Materials, Volume 22, Issue 20, 2012.
The Methodist Hospital Research Institute offers a 10- week Summer Research Program for college undergraduates and medical students in Summer 2012.
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