ISMRM 21st Annual Meeting & Exhibition 20-26 April 2013 Salt Lake City, Utah, USA

Preclinical Cancer Spectroscopy
Friday 26 April 2013
Room 151 AG  10:30 - 12:30 Moderators: E. Jim Delikatny, Lu Jiang

10:30 0804.   
Interplay of Choline Metabolites and Genes in Patient-Derived Breast Cancer Xenografts
Maria T. Grinde1,2, Saurabh S. Gorad1, Nirma Skrbo3,4, Siver A. Moestue1, Einar A. Rødland5, Eldrid Borgan1,6, Alexandr Kristian3, Beathe Sitter1,7, Tone Frost Bathen2,8, Anne Lise Børresen-Dale4,6, Gunhild M. Maelandsmo3,9, Olav Engebråten4,10, Therese Sørlie6, Elisabetta Marangoni11, and Ingrid Susann Gribbestad2,8
1Dept. of Circulation and Medical Imaging, NTNU, Trondheim, Norway, 2St. Olavs University Hospital, Trondheim, Norway, 3Dept. of Tumor Biology, Institute of Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway, 4Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway, 5Dept. of Informatics, University of Oslo, Oslo, Norway, 6Dept. of Genetics, Oslo University Hospital Radiumhospitalet, Oslo, Norway, 7Dept. of Technology, Sør-Trondelag University College, Trondheim, Norway, 8Dept. of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway, 9Dept. of Pharmacy, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway,10Dept. of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway, 11Preclinical Investigation Unit, Translational Research Department, Institut Curie, Paris, France

We employed high-resolution magic angle spinning (HR MAS) MR spectroscopy and gene expression microarray to map the metabolomic and transcriptomic characteristics related to choline metabolism in large panel of patient-derived breast cancer xenografts (N=34) and to evaluate the clinical relevance of xenograft models for metabolomic studies. The results showed significantly different choline metabolic and gene expression profiles in luminal B and basal-like subtypes of breast cancer. It also indicated that the patient-derived xenografts are representative of human breast cancer, and may be valuable for further exploration of subtype-specific metabolic and transcriptomic traits.

10:42 0805.   
IDH1 Mutated Gliomas Exhibit a Distinct 31P MRS Profile -permission withheld
Morteza Esmaeili1, Bob C. Hamans2, Anneke C. Navis3, Remco V. Horssen4, Tone Frost Bathen1, Ingrid Susann Gribbestad5, William P. Leenders3, and Arend Heerschap1,2
1Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway, 2Departments of Radiology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, 3Departments of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, 4Departments of Cell Biology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, 5Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway

Glioma patients harboring the isocitrate dehydrogenase 1 (IDH1) mutation have a better prognosis than those without. As IDH1 regulates several pathways towards lipid synthesis we hypothesized that IDH1 mutant tumors can be identified by 31P-MRS. Localized 31P MR spectra were acquired from four distinct human glioma xenografts including an IDH1mutated model. The IDH1 mutated xenografts were distinguishable from the IDH1wt tumors by significantly higher PC/PE and GPC/GPE ratios. This 31P-spectral profile of the IDH1-mutated model was also observed in extracted tumor tissues and in cell lines expressing mutated-IDH1, and finally in intact human surgical biopsies harboring IDH1-mutation.

10:54 0806.   Lactate and Pyruvate as Mediators of Metabolic Cooperation Between Stromal and Breast Cancer Cells
Ellen Ackerstaff1, Brij B. Patel2, Yanique I. Rattigan2, Natalia Kruchevsky1, John W. Glod2, George Sukenick1, Jason A. Koutcher1, and Debabrata Banerjee2
1Memorial Sloan Kettering Cancer Center, New York, NY, United States, 2The Cancer Institute of New Jersey, RWJMS, UMDNJ, New Brunswick, NJ, United States

Previously, we have shown that cancer-associated fibroblasts (CAFs) take up and metabolize lactate. Here, we hypothesize that breast cancer cells and stromal cells have lactate-mediated metabolic coupling similar to muscle cells, where glycolytic muscle cells secrete lactate that is used by neighboring, oxidative muscle cells as an energy source. Our 13C MRS studies indicate that lactate-metabolizing CAFs secrete 13C-labeled pyruvate. While uptake of exogenous pyruvate in MDA-MB-231 breast cancer cells is increased by cocultured CAFs, subsequent 13C MRS indicates 13C-labeled lactate in the media conditioned by 13C-pyruvate-treated MDA-MB-231 cells, closing the cycle.

11:06 0807.   
Effects of Phosphatidylcholine-Specific Phospholipase C Inhibition on Tumour Growth, Metabolism and HER2 Expression in Preclinical Models of HER-2 Overexpressing Ovarian Cancer
Rossella Canese1, Alessandro Ricci1, Maria Elena Pisanu1, Luisa Paris1, Luisa Altabella1, Emiliano Surrentino1, Marina Bagnoli2, Ludmila Liliac3, Anna Granata2, Silvana Canevari2, Delia Mezzanzanica2, Egidio Iorio1, and Franca Podo1
1Istituto Superiore di Sanità, Rome, RM, Italy, 2Fondazione IRCCS Istituto Nazionale dei Tumori;, Milan, Mi, Italy, 3Morphofunctional Sciences - Histology, University of Medicine and Pharmacy, Iasi, Iasi, Romania

The altered MRS choline profile of human epithelial ovarian cancer (EOC) cells was found to be associated with activation of both choline kinase and phosphatidylcholine-specific phospholipase C (PtdCho-PLC). Inhibition of the latter enzyme by D609 induced decreases in both in vitro cell proliferation and in vivo tumor growth. Quantitative in vivo MRI/MRS examinations and ex-vivo analyses showed marked decreases in the tCho content, increases in the mean T2 and ADC values and decreases in the Ki67 index and HER2 expression in a subset (three out of six) xenografts of SKOV3.ip cells in SCID mice, following intraperitoneal administration of D609.

11:18 0808.   Mutation in Isocitrate Dehydrogenase 1 (IDH1) Leads to Increased T2, ADC and Decreased Lactate and Glutamate in Glioblastoma Model
Jelena Lazovic1, Soto Horacio2, Sichen Li3, Albert Lai3, Linda Liau2, Robert Prins2, Timothy F. Cloughesy4, and Whitney Pope5
1Radiology, University of California at Los Angeles, Los Angeles, CA, United States, 2Neurosurgery, University of California, Los Angeles, CA, United States, 3Neuro-Oncology, University of California, Los Angeles, CA, United States, 4Neuro-Oncology, UCLA, Los Angeles, CA, United States, 5Radiology, University of California, Los Angeles, CA, United States

Recent reports strongly correlate presence of isocitrate dehydrogenase 1 (IDH1) mutation (IDH1-R132) with improved overall survival among glioblastoma patients. This mutation is associated with production of 2-hydroxyglutaric (2-HG) acid, with not well established role in malignant progression. Human glioblastoma cell line (U87) was modified to overexpress mutated isocitrate dehydrogenase 1 (IDH1) R132 in order to determine if 2-hydroxyglutaric acid could be detected in vivo and the consequence on tumor growth and metabolism. We found glioblastoma that overexpressed IDH1-R132 to have significantly increased growth rate along with accumulation of 2-HG and reduction in lactate and glutamate.

11:30 0809.   
Lonidamine Induced Selective Acidification of DB-1 Human Melanoma Xenografts Enhances Tumor Response to Doxorubicin
Kavindra Nath1, David S. Nelson1, Christina Gustafson1, Andrew M. Ho1, Cory Alvey2, Rong Zhou1, Dennis B. Leeper3, and Jerry D. Glickson1
1Radiology, University of Pennsylvania, Philadelphia, PA, United States, 2Pharmacology, University of Pennsylvania, Philadelphia, PA, United States,3Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, United States

Synopsis: The inverted pH gradient between the inside and outside of cells that is observed in tumors presents both obstacles to and opportunities for cancer therapy. As a consequence of their high levels of aerobic glycolysis, DB-1 melanoma xenografts exhibit a selective decrease in their intracellular pH by ~0.6 units following treatment with the lonidamine (LND), which inhibits the export of lactic acid from the tumor cell via the monocarboxylic acid transporter (MCT). In addition, LND decreases the bioenergetics state of the tumor by inhibiting transport of pyruvate into mitochondria via the mitochondrial pyruvate carrier (MPC). Under these conditions, doxorubicin accumulates in the tumor as a result of protonation of its amino group (i.e., cation trapping), which produces a pronounced enhancement of the antineoplastic activity of this anthracycline. Treatment of DB1 melanomas with doxorubicin following tumor acidification with LND produced long-term (>50 day) growth delays in four out of five melanoma xenografts demonstrating the potential clinical utility of combining LND with doxorubicin in the treatment of melanoma and other human cancers.

11:42 0810.   Hypoxia Enhances De Novo Fatty Acid Synthesis from Glutamine and Reduces De Novo Fatty Acid Synthesis from Glucose in TSC2-/- Mouse Fibroblasts
Anthony Mancuso1, Regina M. Young2, Brian D. Keith3, Craig B. Thompson4, and M. Celeste Simon2
1Cancer Biology/Radiology, University of Pennsylviania, Philadelphia, PA, United States, 2Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, United States, 3Cell and Molecular Biology, University of Pennsylvania, Philadelphia, PA, United States, 4Sloan Kettering Institute, New York, NY, United States

The effects of hypoxia on de novo lipogenesis in TSC2-/- mouse fibroblasts were examined with uniformly labeled 13C glucose and glutamine. These cells are a model for cancers with oncogenes that dis-regulate the akt/mTOR signaling cascade. The results demonstrate that both glucose and glutamine are important for de novo lipogenesis of both saturated and unsaturated fat under normoxic conditions. Hypoxia caused a marked reduction for both saturated and unsaturated lipid synthesis from glucose but not glutamine. The results have important implications for the design of anti-cancer therapies that target lipogenesis, for tumors with significant levels of hypoxia.

11:54 0811.   
Combining MRSI and Mass Spectrometric Imaging Reveals Protein Biomarkers in Breast Tumor Models
Lu Jiang1, Kamila Chughtai2, Tiffany Greenwood1, Gert Eijkel2, Ron Heeren2, and Kristine Glunde3
1Division of Cancer Imaging Research, Department of Radoilogy, Johns Hopkins School of Medicine, BALTIMORE, MD, United States, 2FOM-Institute AMOLF, Amsterdam, Netherlands, 3Division of Cancer Imaging Research, Department of Radoilogy, Johns Hopkins University, BALTIMORE, MD, United States

The intensity of the total choline (tCho) signal in magnetic resonance spectroscopic imaging (MRSI) of tumors is spatially heterogeneous. In vivo H1 MRSI with the spectral resolution to resolve the components of the tCho signal and its membrane precursors is currently unavailable. Mass spectrometry imaging (MSI) of histologic tumor sections is able to detect thousands of molecules from the tissue surface. We have investigated the correlations between tCho and peptides in a human breast cancer model by combining in vivo MRSI with ex vivo MSI, which identified specific peptide species that are spatially correlated with tCho.

12:06 0812.   
Establishment of Patient-Derived Models of Renal Cell Carcinoma to Study Metabolism and Develop Relevant Clinical Biomarkers
Renuka Sriram1, Kayvan R. Keshari1, Mark Van Criekinge1, John Kurhanewicz1, David M. Wilson1, Donna M. Peehl2, and Zhen J. Wang1
1University of California, San Francisco, San Francisco, CA, United States, 2Stanford University, Palo Alto, CA, United States

Renal cell carcinomas (RCCs) are a heterogeneous group of tumors with a wide range of aggressiveness. There is a current lack of noninvasive biomarkers that can confidently predict the behavior of RCCs to guide treatment selection and to monitor treatment response. Development of clinically relevant biomarkers of RCC aggressiveness and response to novel therapeutics requires robust models that recapitulate the human situation. The purpose of this study is to establish both an ex vivo and an in vivo model of RCCs using patient-derived tissue slices for metabolism studies in conjunction with hyperpolarized (HP) 13C MR.

12:18 0813.   Inhibition of Prostate Cancer Growth by Deferiprone
Rui V. Simoes1, Natalia Kruchevsky1, Inna Serganova2, Ellen Ackestaff1, George Sukenick3, Ronald G. Blasberg2,4, and Jason A. Koutcher1,5
1Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, United States, 2Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, United States, 3NMR Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, United States, 4Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, United States, 5Weill Cornell Medical College, Cornell University, New York, NY, United States

Activation of mitochondrial aconitase (m-acon) is an early biochemical change during prostate cancer (PCa) development, leading to a shift from citrate-producing to a citrate-oxidizing malignant phenotype. Deferiprone (DFP), an iron chelator used in the clinic has been shown to impair aconitase activity and inhibit cell growth. We have studied the effects of DFP on TRAMP C2 cells. DFP induced a marked decrease in TRAMP C2 cell growth (IC50=49 M), affecting many metabolic parameters detected by 31P and 13C-MRS, and decreasing cellular oxygen consumption. Our results show the potential of DFP to inhibit PCa growth at clinically relevant doses.