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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.

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.

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.

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.

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

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.

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.

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.

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.

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