Room 151 AG

10:30 - 12:30

Moderators:

E. Jim Delikatny, Lu Jiang

Maria T. Grinde^1,2, Saurabh S. Gorad¹, Nirma Skrbo^3,4, Siver A. Moestue¹, Einar A. Rødland⁵, Eldrid Borgan^1,6, Alexandr Kristian³, Beathe Sitter^1,7, Tone Frost Bathen^2,8, Anne Lise Børresen-Dale^4,6, Gunhild M. Maelandsmo^3,9, Olav Engebråten^4,10, Therese Sørlie⁶, Elisabetta Marangoni¹¹, and Ingrid Susann Gribbestad^2,8
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.

Morteza Esmaeili¹, Bob C. Hamans², Anneke C. Navis³, Remco V. Horssen⁴, Tone Frost Bathen¹, Ingrid Susann Gribbestad⁵, William P. Leenders³, and Arend Heerschap^1,2
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.

Ellen Ackerstaff¹, Brij B. Patel², Yanique I. Rattigan², Natalia Kruchevsky¹, John W. Glod², George Sukenick¹, Jason A. Koutcher¹, and Debabrata Banerjee^2
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.

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 Podo^1
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.

Jelena Lazovic¹, Soto Horacio², Sichen Li³, Albert Lai³, Linda Liau², Robert Prins², Timothy F. Cloughesy⁴, and Whitney Pope^5
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.

Kavindra Nath¹, David S. Nelson¹, Christina Gustafson¹, Andrew M. Ho¹, Cory Alvey², Rong Zhou¹, Dennis B. Leeper³, and Jerry D. Glickson^1
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.

Anthony Mancuso¹, Regina M. Young², Brian D. Keith³, Craig B. Thompson⁴, and M. Celeste Simon^2
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.

Lu Jiang¹, Kamila Chughtai², Tiffany Greenwood¹, Gert Eijkel², Ron Heeren², and Kristine Glunde^3
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.

Renuka Sriram¹, Kayvan R. Keshari¹, Mark Van Criekinge¹, John Kurhanewicz¹, David M. Wilson¹, Donna M. Peehl², and Zhen J. Wang^1
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.

Rui V. Simoes¹, Natalia Kruchevsky¹, Inna Serganova², Ellen Ackestaff¹, George Sukenick³, Ronald G. Blasberg^2,4, and Jason A. Koutcher^1,5
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.