The Methodist Hospital Research Institute Physical Sciences-Oncology Center
The Methodist Hospital Research Institute, Houston, TX
Center Summary:
The Methodist Hospital Research Institute Physical Sciences-Oncology Center will evaluate the process of mass transport in cancer to generate novel methods to improve diagnosis and treatment of cancer. This center will focus on two specific cancer types: colorectal cancer, the second leading cause of cancer death in the U.S., and liver metastasis, the most common site of metastatic disease. These investigators will integrate mathematics, innovative engineered transport probes and state-of-the-art imaging to elucidate the transport physics of various physical and biological barriers related to tumorigenesis and drug delivery. Notably, this trans-disciplinary team will study the physical barriers to the evolution of liver metastasis from colorectal cancer and the administration of novel carriers to surpass these barriers. Ultimately, these studies will provide a clearer grasp of the function and physics of biological barriers, and in turn will accelerate basic discovery and assist in the design for potential therapeutics.
Project 1 – Directed transport physics and multi-scale therapy of colon cancer liver metastasis
Project Leaders: Mauro Ferrari (The Methodist Hospital Research Institute), Isaiah Fidler (U.T. M.D. Anderson Cancer Center), and Renata Pasqualini (U.T. M.D. Anderson Cancer Center)
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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 of colorectal cancer (CRC) 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 CRC 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 (U.T. M.D. Anderson Cancer Center) and Lon Wilson (William Marsh Rice University)
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PROJECT 2 will explore issues related to the progression kinetics of a primary hepatic tumor (hepatocellular carcinoma), 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 will 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 will be 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 – Study of the biophysical mechanisms regulating the efficacy of orally administered anti-cancer therapeutics from engineered nanocarriers
Project Leader: Nicholas Peppas (University of Texas- Austin)
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PROJECT 3 is dealing with various physical barriers that chemotherapeutical agent administered orally meets on its way to be systemically absorbed and to reach the target tumor tissue. These barriers include for example: changes in pH across the gastrointestinal (GI) tract, enzymatic degradation, and epithelial transport through different mechanisms.
To study and tackle these barriers we will use our engineered polymeric carriers. The engineered delivery vehicle capable of being loaded with the target compound and subsequently releasing it, with attention focused to the efficiency of each physical process involved, must first be designed and tested for facing each of the physical barriers components. The pH increase that occurs when passing from the stomach to the upper small intestine is the trigger to initiate release so this carrier must be able to selectively release the compound in response to a pH shift used to simulate this physiological event. The kinetics of release from the carrier must be appropriate given the projected residence time for the carrier particles in the region of the digestive tract most suitable for absorption of the therapeutic agent.
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.
Core 1 - BioSimulation Core
| Core Leaders: |
Vittorrio Cristini (The University of New Mexico) |
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Paolo Decuzzi (The Methodist Hospital Research Institute) |
The core will provide 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: |
Rebecca Richards-Kortum (William Marsh Rice University) |
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Seok-Hyun Yun (Harvard University/Mass General Hospital) |
The broad goals of the Advanced Intravital Microscopy Core are to provide the three projects with 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. The Core will be established in Boston within the Wellman Center for Photomedicine at Massachusetts General Hospital (MGH). The laboratory space is well suited for live animal imaging, with its own dedicated mouse facility connected to the imaging facility on the same floor and proximity to the MGH animal facility located in the basement of the building, and routine intravital microscopy experiments will be carried out in Houston within the new CABIR building where a room for this activity has been allocated and specifically designed.
Mauro Ferrari, Ph.D.
Dr. Ferrari serves as President and CEO of The Methodist Hospital Research Institute, where he holds the Ernest Cockrell Jr. Distinguished Endowed Chair. He is also Professor of Internal Medicine at the Weill Cornell Medical College, Adjunct Professor of Experimental Therapeutics The University of Texas M.D. Anderson Cancer Center, Professor of Bioengineering at Rice University, Adjunct Professor of Biomedical Engineering at UT Austin, and President of The Alliance for NanoHealth in Houston.
Dr. Mauro Ferrari is a founder of biomedical nano/micro-technology, especially in their applications to drug delivery, cell transplantation, implantable bioreactors, and other innovative therapeutic modalities. In these fields, he has published more than 200 peer-reviewed journal articles and 6 books. He is the inventor of more than 30 issued patents, with about thirty more pending in the US and internationally. His contributions have been recognized by a variety of accolades, including: the Presidential Young Investigator Award of the National Science Foundation; the Shannon Director's Award of the National Institutes of Health; the Wallace H. Coulter Award for Biomedical Innovation and Entrepreneurship; and the Italiani nel Mondo Award from the Italian Ministry of Foreign Affairs. His career research and development portfolio totals over $50 million, including support from the NCI, NIH, DoD, NASA, NSF, DARPA, DoE, the State of Texas, and the State of Ohio, The Ohio State University, and several private enterprises. He 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, Professor of Internal Medicine, Mechanical Engineering, Materials Science and Associate Vice President, Health Sciences Technology and Commercialization, Associate Director of the Dorothy M. Davis Heart and Lung Research Institute and Director of the Biomedical Engineering Center. Upon recruitment to Houston, he served as Professor and Chair of the Department of Nanomedicine at the University of Texas Health Science Center.
Dr. Ferrari also served as Special Expert on Nanotechnology at the National Cancer Institute in 2003-2005, 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.
Dr. Ferrari is an academic- entrepreneur, with several companies that originated from his laboratory. He currently serves on the Board of Director three companies: Nanomedical Systems of Austin TX; Leonardo Biosystems of Houston TX, and NASDAQ-traded Arrowhead Research Corporation (NASDAQ:ARWR).
Steven A. Curley, M.D.
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.
