|Metabolic & Functional Assessment of Cancer Treatment: Animal Models|
Assessment of Radiation Mediated Gene Therapy Via
Chad Roland Haney1, Adrian D. Parasca1, Rebecca Bell1, Marta Zamora1, Xiaobing Fan1, Gregory S. Karczmar1, Helena J. Mauceri1, Ralph R. Weichselbaum1, Howard J. Halpern1, Charles A. Pelizzari1
1University of Chicago, Chicago, Illinois, USA
Imaging techniques are under development which, are intended to facilitate early analysis of spatial patterns of tumor response to combined radiation and antivascular gene therapy. Changes of vascular permeability and perfusion maps using Dynamic-contrast-enhanced MRI, and tissue oxygenation measurements using electron paramagnetic resonance imaging were registered to characterize a “signature” for response. This is the first report of quantitative, absolute oxygen measurements being correlated with tissue perfusion, in vivo and non-invasively. Radiation mediated antivascular gene therapy appears to significantly improve tissue oxygenation by normalizing perfusion, i.e., decreasing uptake and increasing washout of contrast agent.
In Vivo 19F MRS Detection of Carboxypeptidase
G2 Activity <
Yann Jamin1, Lynette Smyth2, Simon P. Robinson1, Thomas R. Eykyn1, Caroline J. Springer2, Martin O. Leach1, Geoffrey S. Payne1
1Institute of Cancer research and Royal Marsden NHS trust, Sutton, UK; 2Institute of Cancer Research, Sutton, UK
Carboxypeptidase G2 is used in Gene Directed Enzyme Prodrug Therapy, a promising gene therapy strategy for cancer treatment to activate non toxic prodrugs into cytotoxic DNA alkylating agents. We report in vivo non-invasive 19F MRS detection of Carboxypeptidase G2 activity following intravenous injection of 3,5-Difluorobenzoylglutamic acid (3,5-DFBGlu) in mice bearing xenografts derived from human colon adenocarcinoma WiDr cells stably expressing CPG2. The high signal-to-noise ratio afforded by the two equivalent 19F nuclei of 3,5-DFBGlu allows the 19F 3D spectroscopic imaging to image the location of CPG2 activity.
Non-Invasive Detection of Tumor Cell
Death - Comparison Between FDG and Hyperpolarized 13C-Labelled Pyruvate
Timothy Howard Witney1, 2, Sam E. Day3, Mikko I. Kettunen1, 2, Andre A. Neves1, 2, Ferdia A. Gallagher1, 2, Jan H. Ardenkjaer-Larsen4, Kevin M. Brindle1, 2
1University of Cambridge, Cambridge, UK; 2CRUK Cambridge Research Institute, Cambridge, UK; 3National Institutes of Health, Bethesda, USA; 4GE Healthcare, Amersham, UK
The aim of this study was to monitor tumor response to treatment, comparing uptake and metabolism of hyperpolarized 13C-labelled pyruvate to the uptake of [14C]FDG in EL4 cells. Induction of cell death by etoposide lead to a progressive decrease in the lactate dehydrogenase-catalyzed pyruvate/lactate flux. This coincided with a loss of the cellular NAD(H) pool and a marked increase in the number of apoptotic cell. A similar decrease in [14C]FDG uptake was observed following treatment. The results suggest that 13C-labelled pyruvate may be useful for detecting early responses of tumours to chemotherapy.
Phosphorus MRS Effectively Monitors Lentiviral-Mediated
Gene Therapeutic Silencing of Choline Kinase in a Human Breast Cancer
Kristine Glunde1, Balaji Krishnamachary1, Flonne Wildes1, Venu Raman1, Zaver M. Bhujwalla1
1The Johns Hopkins University School of Medicine, Baltimore, USA
Choline kinase (Chk) overexpression contributes to the elevated phosphocholine (PC) and phosphomonoester (PME) levels detected in breast cancers. Chk is currently being explored as target for anticancer therapy. Here we have used in vivo single-voxel 31P MRS to monitor and evaluate an optimal treatment regimen for systemic delivery of lentiviral particles that silence Chk by Chk-specific short-hairpin RNA. Bi-weekly intravenous administration of these lentiviral particles significantly decreased tumor growth of breast cancer xenografts. Decreased tumoral PC and PME levels demonstrated a successful functional therapeutic response, as monitored noninvasively by 31P MRS in vivo.
Tracking Chemotherapy-Induced Changes in Tumor
Antigen Expression in a Pre-Clinical Breast Cancer Model
Zdravka Medarova1, Leonid Rashkovetsky1, Pamela Pantazopoulos1, Anna Moore1
1Massachusetts General Hospital, Charlestown, Massachusetts, USA
A key goal of cancer research is to monitor and predict the response to treatment. Considering the variability of the response, this has to be accomplished on a patient-by-patient basis. With this in mind, we applied magnetic resonance imaging to monitor the expression of a tumor-specific antigen (uMUC-1), found on over 90% of breast cancers and predictive of chemotherapeutic response. As a contrast agent, we employed an imaging probe (MN-EPPT) targeting uMUC-1. MN-EPPT consists of superparamagnetic iron oxide nanoparticles (MN) for MR imaging, modified with Cy5.5 dye (for fluorescence optical imaging), and conjugated to peptides (EPPT), specifically recognizing uMUC-1
Vessel Size Index MRI with Viable Tumor Analysis for
Monitoring Anti-Angiogenic Therapeutics
Sharon E. Ungersma1, Sharon Fong Yee1, Glenn Pacheco1, Germaine Fuh1, Joan M. Greve1, Franklin V. Peale Jr. 1, Sarajane Ross1, Richard A. D. Carano1
1Genentech, Inc., South San Francisco, California , USA
Vessel size index (VSI) MRI determines fractional blood volume and mean vessel size on a voxel-by-voxel basis using changes in T2 and T2* caused by the introduction of an iron oxide contrast agent. In this study, we use VSI MRI to examine the effect of G6-31, an anti-VEGF-A monoclonal antibody. To account for tumor heterogeneity, we restrict the VSI parameter analysis to the viable tumor tissue as determined with multispectral clustering. The viable tissue technique requires no additional scans beyond those used for VSI MRI and can improve accuracy of tumor parameter measurement by eliminating necrotic regions from the analysis.
Time-Resolved MRA Assessment of Pulmonary
Toxicity in a Rabbit Model of Stereotactic Lung Radiation Therapy:
Preliminary Results on the Efficacy of a Radioprotector
Jaime Mata1, Ke Sheng1, Paul Read1, Klaus Hagspiel1, Kai Ruppert2, Anthony Soltis1, James Brookeman1, John Mugler III1
1University of Virginia, Charlottesville, USA; 2University of Pennsylvania, Philadelphia, USA
Radiation-induced pulmonary symptoms occur in approximately 20% of patients who receive radiation treatment for cancer of the lung or breast. Presently, there is no clinical test available to predict toxicity or to assess the extent of radiation-induced lung injury early after treatment. However, early detection might allow for preventative therapy to reduce toxicity and, if early lung damage could be detected during radiotherapy, this would allow a change in the plan prior to extensive damage. In this work we report the use of time-resolved MRA to assess the efficacy of a radioprotector in limiting radiation toxicity in a rabbit model of stereotactic-radiation pulmonary injury.
DCE-MRI Provides Evidence for Vascular Effects of AMG
386, a First-In-Class Anti-Angiogenic Peptibody That Specifically
Inhibits Interaction of Angiopoietins-1 and -2 with Tie-2
Yuying C. Hwang1, Ed Ashton2, Lee Rosen3, Roy Herbst4, Jeffrey Silverman5, Ngocdiep Le1, Erik Rasmussen1, Jon Oliner1, Juan Leal6, Robert Radinsky1, Ji-Rong Sun1, Jeff Evelhoch1, Ed Jackson4
1Amgen Inc., Thousand Oaks, California , USA; 2VirtualScopics Inc., Rochester, New York, USA; 3Premiere Oncology, Santa Monica, California , USA; 4The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA; 5Landmark Imaging, Los Angeles, California , USA; 6University of Minnesota, Twin Cities, Minnesota, USA
AMG 386 is a peptide-fc fusion protein (peptibody) that specifically inhibits the interaction of angiopoietins-1 and -2 (Ang1/2) with Tie-2 receptor. We performed DCE-MRI in Colo205 xenografts and in the first in human (FIH) clinical trial to study the effect of AMG 386 on tumor vasculature. Both pre-clinical and clinical DCE-MRI results demonstrate a significant vascular effect of this first-in-class anti-angiogenic investigational drug that provides highly potent and selective inhibition of angiopoietins, even though the vascular effects are not as dramatic as for VEGF-targeted molecules.
Using BOLD MRI with Carbogen to Evaluate Tumour
Response to Antiangiogenic Therapy
Simon Walker-Samuel1, Lesley D. McPhail1, Anderson J. Ryan2, Simon P. Robinson1
1Institute of Cancer Research, Sutton, UK; 2AstraZeneca, Macclesfield, UK
Biomarkers derived from blood oxygen level dependent (BOLD) MRI with carbogen and diffusion MRI were used to assess the acute effects of an antiangiogenic agent (vandetanib, AstraZeneca) in murine PC3 xenografts. Following therapy, a significant decrease was observed in both median baseline (pre-carbogen) R2* and median ÄR2* (the change in R2* induced by carbogen), suggesting improved blood flow and a decrease in tumour deoxyhaemoglobin. No significant change in the apparent diffusion coefficient was observed. These results are consistent with the proposed hypothesis of vascular normalisation, in which the efficacy of tumour vasculature is temporarily improved following antiangiogenic therapy.
Diffusion Weighted Imaging as Predictor of Therapy
Response in Animal Model of Ewing-Sarcoma
Wilfried Reichardt1, Udo Kontny1, Markus Uhl1, Dominik von Elverfeldt1
1University of Freiburg, Freiburg, Germany
Diffusion weighted imaging (DWI) has proved to be a valuable tool in monitoring the effect of chemotherapy in clinical as well as in preclinical studies. Especially early assessment of treatment induced changes using DWI seems to be a promising tool in the evaluation of novel therapies. High dose chemotherapy in Ewing’s sarcoma has been demonstrated to be associated with higher cure rates than conventional chemotherapy in relapsed patients. The goal of this Study was to evaluate diffusion-weighted magnetic resonance imaging for monitoring dose dependent tumour response in mouse-xenograft model of Ewing’s Sarcoma after administration of Treosulfan in different dosages