Preclinical Studies on Cancer
Tuesday 21 April 2009
Room 313A 10:30-12:30


Zaver M. Bhujwalla and John R. Griffiths

10:30  192. Unraveling Mouse Glioma Heterogeneity with DCE-T1 MRI and 1H-CSI Metabolome Pattern Perturbation
    Rui Vasco Simões1,2, Maria Luisa García-Martín3, Teresa Delgado-Goñi1,4, Silvia Lope-Piedrafita4,5, Carles Arús1,4
Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain; 2Bioquímica, Universidade de Coimbra, Coimbra, Portugal; 3Resonancia Magnética, Clínica Nuestra Señora del Rosario, Madrid, Spain; 4CIBER-BBN, Cerdanyola del Vallès, Spain; 5Servei de Resonància Magnètica Nuclear, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain
    In this work we have investigated the heterogeneity of GL261 mouse glioma (n=9) microenvironments in vivo by correlating the information obtained from dynamic contrast-enhanced T1 MRI (DCE-T1) with that from dynamic 1H-CSI during an acute hyperglycemic challenge. The distinct enhancement patterns given by DCE-T1 and 1H-CSI maps (MR-detectable glucose and lactate) suggest different vascularization/permeability and metabolism, respectively, in the different regions of each studied tumor. Other metabolome challenges should be tested to better understand GL261 in vivo sampled glioma regional heterogeneity.


10:42 193.

Metabolic Imaging of Cachectic Tumors

    Marie-France Penet1, Samata Kakkad1, Dmitri Artemov1, Zaver M. Bhujwalla1
Department of Radiology and Radiological Science, JHU ICMIC Program, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
    Cachexia occurs with a high frequency in several cancers. The significant weight loss resulting from this condition causes impairment of immune function, poor outcome of chemotherapy, fatigue, and markedly reduced quality of life. The ability to noninvasively identify cachexia-inducing tumors, and understand the metabolic characteristics of these tumors is important for determining new targets to arrest or reverse this condition. Here we report on the metabolic differences, identified by 1H magnetic resonance spectroscopy (MRS), between cachectic and non-cachectic tumors.
10:54 194. Magnetic Resonance Imaging Reveals the Progression, Regression and Indolence of in Situ Carcinoma in Transgenic Mice.
    Sanaz Arkani Jansen1, Suzanne Conzen2, Xiaobing Fan, Erica Markiewicz, Gillian Newstead, Gregory Karczmar1
University of Chicago, Chicago, IL, USA; 2Medicine, University of Chicago
    The processes that trigger progression of preinvasive ductal carcinoma in situ (DCIS) to invasive breast cancer remain elusive. Given the necessity of surgical excision of newly-diagnosed DCIS, studying natural history of disease in women is nearly impossible. Here, we use MRI to track in vivo  the transition of in situ  to invasive cancer in transgenic mice. Significantly, we found direct evidence that DCIS is a non-obligate precursor: some lesions do not progress to invasive tumors, and some even regress. This sets the stage for future studies evaluating the efficacy of preventive therapy for progression of DCIS.


11:06 195. Novel Nitroimdazolyl Derivatives and Its Reduction Products Reveal Hypoxia in Cultures of C6 Cells Using 1H HR MAS
    Jesus Pacheco-Torres1,2, Paloma Ballesteros2, Sebastian Cerdan3, Pilar Lopez-Larrubia3
Instituto de Investigaciones Biomédicas "Alberto Sols" - CSIC , Madrid, Spain; 2Instituto Universitario de Investigación - UNED, Madrid, Spain; 3Instituto de Investigaciones Biomédicas "Alberto Sols" - CSIC, Madrid, Spain
    We describe a novel nitroimidazolyl derivative as a probe for the measurement of hypoxia by 1H MRS methods. We show that our nitroimidazole has a redox potential similar to NADP and that is reduced by the cytochrome P-450 reductase system under anoxic conditions. In cultures of C6 cells under hypoxic conditions, the compound shows at least two reduction products that are originated in a hypoxia dependent manner. These results are validated with those obtained with pimonidazole, a commercial hypoxia probe. The kinetics of the reduction process may be observed by 1H HR MAS spectroscopy
11:18 196. In Vivo Imaging of Tumor Hypoxia Using 19F MRS of Trifluoromisonidazole
    Ellen Ackerstaff1, Mihai Coman1, Sean Carlin1, Sean A. Burke1, Kristen L. Zakian1, Khushali Kotedia1, Joseph O'Donoghue1, Clifton C. Ling1, Jason A. Koutcher1
Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
    Tumor hypoxia has been related to treatment response. We used in vivo 19F-MRS/MRSI of Trifluoromisonidazole (TF-MISO) to evaluate tumor hypoxia in two animal tumor models. Intratumoral TF-MISO concentrations were only moderately influenced by tumor growth in both tumor models. The breathing of 21%O2, 95%O2/5%CO2, or 100%O2 did not significantly influence intratumoral TF-MISO levels in the MCa tumor, whereas in R3327-AT tumors, breathing of 100%O2 decreased significantly intratumoral TF-MISO levels in tumors below ~600mm3. Our results suggest that hypoxia imaging by 19F MR of TF-MISO may help to identify tumors that can be successfully reoxygenated and, thus, sensitized for radiation therapy.
11:30 197. Molecular Characterization of the Relationship Between Hypoxia, Total Choline and Breast Cancer Stem Cell Markers

Balaji Krishnamachary1, Marie-France Penet1, Sridhar Nimmagadda1, Meiyappan Solaiyappan1, Dmitri Artemov1, Kristine Glunde1, Arvind P. Pathak1, Paul Winnard1, Venu Raman1, Martin Pomper1, Zaver M. Bhujwalla1
1JHU ICMIC Program, The Russell H. Morgan Department of Radiology and Radiological Science, The Jonhs Hopkins University School of Medicine, Baltimore, MD, USA

    We previously observed an association between hypoxia, total choline, and increased expression of CD44, a marker associated with stem-like breast cancer cells. Here we have validated our observations that hypoxia is strongly associated with several stem-like breast cancer cell markers, and confirmed with imaging, that increased total choline and hypoxia are co-localized in MDA-MB-231 breast cancer xenografts. These data suggest that noninvasive imaging of hypoxia can identify regions most likely to contain stem-like breast cancer cells, and that hypoxic environments and choline metabolism may be targeted to reduce stem-like cell burden and minimize tumor recurrence.
11:42 198. Glycine as a Biomarker in Brain Tumors
    Valeria Righi1,2, Dionyssios Mintzopoulos1,2, Ovidiu C. Andronesi2, Peter M. Black3, A Aria Tzika1,2
NMR Surgical Laboratory, MGH & Shriners Hospitals, Harvard Medical School, Boston, MA, USA; 2Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Boston, MA, USA; 3Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
    We employed high-resolution magic angle spinning proton MR spectroscopy (HRMAS H1 MRS) to evaluate glycine as a biomarker for brain tumors. Glycine in combination with myo-inositol was useful for differentiating glioblasoma multiforme from metastatic brain tumors.


11:54 199. Initial Metabolomic Analysis of Glioblastoma Multiforme Subtypes by HRMAS
    Daniel Valverde-Saubí1,2, Ana Paula Candiota1,2, Maria Antònia Molins3, Miguel Feliz3, Óscar Godino4, Juan Martino4, Juan José Acebes2,4, Carles Arús1,2
Bioquímica i Biologia molecular, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain; 2Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Cerdanyola del Vallès, Barcelona, Spain; 3Servei RMN Parc Científic de Barcelona, Universitat de Barcelona, Barcelona, Spain; 4Servei de Neurocirurgia, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain
    The aim of this study was to identify possible metabolomic glioblastoma multiforme subtypes using High Resolution Magic Angle Spinning Spectroscopy. According to our results, we detect three different glioblastoma multiforme which may bear some relationship to different proliferation rates.


12:06 200. Comparison of MRS with Fluorescence for Molecular Imaging and Determination of Phospholipase Isoforms
    Daniel-Joseph Leung1, Theresa Mawn1, Edward James Delikatny1
Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA
    We present the modulation of MR-visible metabolic response through the inhibition of the calcium-independent phospholipase A2 (iPLA2) and the cytosolic phospholipase A2 (cPLA2) isoforms and their differential roles in mediating lipid responses using the specific inhibitors BEL and AACOCF3, respectively. At the same time, a separate pathway of overall phospholipase A2 (sPLA2 isoform) activity is shown by kinetic fluorescence activation in vitro. This not only suggests the possibility of using MRS and optical methods to compare findings, but also the ability to characterize enzyme isoforms relevant to tumor drug response collaterally.
12:18 201. Detection of Lung Metastases Using Hyperpolarized 3He MRI and Targeted Magnetic Nanoparticles – Histologic Validation and Detection Limits

    Rosa Tamara Branca1, Zackary Cleveland2, Boma Fubara2, Challa Kumar3, Carola Leuschner4, Warren Sloan Warren5, Bastiaan Driehuys2
Center for molecular and biomolecular imaging, Duke University , Durham, NC, USA; 2Center for in vivo microscopy, Duke University, Durham, NC, USA; 3Center for Advanced Microstructures and Devices, Louisiana State University, Baton Rouge, LA, USA; 4William Hansel Cancer Prevention, Pennington Biomedical Research Center, Baton Rouge, LA, USA; 5Center for molecular and biomolecular imaging, Duke University, Durham, NC, USA

Breast and prostate metastases are detected in lungs using hyperpolarized helium MRI and targeted contrast agent. The method allows the detection of metastatic nodules smaller than 100 micrometers with high specificity and sensitivity and, more generally, can be used to detect and track any type of labeled cell in lungs