ISMRM 23rd Annual Meeting & Exhibition • 30 May - 05 June 2015 • Toronto, Ontario, Canada

Scientific Session • Cancer Preclinical: Cells & Animals

Wednesday 3 June 2015

Room 701 A

10:00 - 12:00


Kristine Glunde, Ph.D., Sabrina M. Ronen, Ph.D.

10:00 0522.   Metabolic signatures of colorectal cancer in biofluids: NMR-based metabolomics of fecal extracts
Yan Lin1, Changchun Ma2, Zhiwei Shen1, zhening wang1, and Renhua Wu1
1Radiology Department, Second Affiliated Hospital, Shantou University Medical College, Shantou City, Guangdong Province, China, 2Radiation Oncology, Cancer Hospital, Shantou University Medical College, Guangdong Province, China

This present study is a NMR-based metabolomics approaches coupled with orthogonal projection to least squares discriminant analysis (OPLS-DA) to evaluate the ability to characterize the metabolic ˇ°fingerprintˇ± of fecal extracts from patients with colorectal cancer (CRC) on larger patient cohorts. The most significant metabolites for classification include short-chain fatty acids, alanine, isoleucine, leucine, valine, glutamate, glycerol, suggesting changes in the gut microbial community or malabsorption. These results shows the valuable potential of NMR-based metabonomics of fecal extracts to characterize the systemic metabolic disturbances underlying CRC and to identify possible early biomarkers for clinical prognosis.

10:12 0523.   Ethanolamine Kinase-1 is the major contributor to Phosphoethanolamine Levels in Breast Cancer Cells
Tariq Shah1, Balaji Krishnamachary1, Flonne Wildes1, Jannie Wijnen2, Kristine Glunde1, and Zaver M Bhujwalla1
1Division of Cancer Imaging Research, Johns Hopkins University, Baltimore, Maryland, United States, 2University Medical Centre Utrecht, Cancer center, Utrecht, Netherlands

In understanding the aberrant choline metabolism of cancer significant effort has been focused on phosphocholine (PC) but the role of phosphoethanolamine (PE) is relatively underexplored even though tumors show increased PE as consistently as increased PC. Here we have used siRNAs to silence specific genes involved in choline and ethanolamine metabolism to understand their roles in intracellular metabolite levels measured with high-resolution 31P MR spectroscopy of cell extracts. We have demonstrated that ethanolamine kinase-1 (EthnK-1) is the major contributor to PE levels observed in vivo and may be a potential therapeutic target.

10:24 0524.   
A theranostic probe to image choline kinase expression and inhibition in a breast cancer model
Sean P Arlauckas1, Manoj Kumar1, Anatoliy V Popov1, Harish Poptani1, and Edward J Delikatny1
1Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States

To better understand the changes in choline observed using in vivo MRS, an optical imaging contrast agent was developed to report choline kinase levels.

10:36 0525.   TMPRSS2:ERG gene fusion and ERG overexpression in human prostate cancer are associated with changed metabolism
Ailin Falkmo Hansen1, Elise Sandsmark1, Morten Beck Rye2,3, Alan Wright4, Helena Bertilsson2,5, Anna M. Bofin6, Anders Angelsen1, Tone Frost Bathen1, and May-Britt Tessem1,3
1Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway, 2Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway, 3St. Olavs Hospital, Trondheim, Norway,4Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom, 5Department of Urology, St. Olavs Hospital, Trondheim, Norway, 6Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway

TMPRSS2-driven overexpression of ERG has been shown to be associated with several markers for prostate cancer aggressiveness, although its clinical significance is not fully understood. The aim of this study was to investigate metabolic alterations associated with ERG overexpression/TMPRSS2:ERG to increase the biological understanding of TMPRSS2:ERG fusion in prostate cancer patients. Prostate tissue samples (n=95) and prostate biopsy samples (n=40) were analyzed by 1H HR-MAS MRS. In ERG-high samples, citrate and spermine were significantly decreased compared to ERG-low samples. These results were validated in biopsy samples by FISH-detected TMPRSS2:ERG and suggest altered citrate and spermine metabolism due to ERG overexpression/TMPRSS2:ERG.

10:48 0526.   
Reduced production of hyperpolarized 5-13C-glutamate is associated with the IDH1 mutation
Jose Luis Izquierdo Garcia1, Pavithra Luis Viswanath1, Pia Eriksson1, Marina Radoul1, Larry Cai1, Myriam M Chaumeil1, Russell O Pieper2, Joanna J Phillips2, and Sabrina M Ronen1
1University California San Francisco, San Francisco, California, United States, 2Department of Neurological Surgery, Helen Diller Research Center, University California San Francisco, San Francisco, California, United States

This study investigated the role that mutant IDH1-driven metabolic reprogramming plays in tumorigenesis. We investigated hyperpolarized 5-13C-glutamate production from hyperpolarized 2-13C-pyruvate in mutant and wild-type cells and found that glutamate production was significantly reduced in mutant cells, associated with a drop in PDH activity. Treatment with dichloroacetate, a PDH agonist, significantly increased HP 5-13C-glutamate production with an accompanying decrease in clonogenicity. Our results indicate that HP 5-13C-glutamate can serve as a metabolic imaging biomarker of PDH down-regulation in IDH1 mutant glioma cells.

11:00 0527.   Tumor invasion visualized by neurochemical profile modification in human GBM induced by cancer stem cells in mice: 1H-MRS longitudinal study - permission withheld
Mor Mishkovsky1, Cristina Cudalbu2, Irene Vassallo3, Marie-France Hamou3, Arnaud Comment4, Monika Hegi3, and Rolf Gruetter1,2
1Laboratory of Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland, 2Center of biomedical imaging (CIBM), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland, 3Laboratory of Brain Tumor Biology and Genetics, Department of Neurosurgery, Lausanne University Hospital, Lausanne, Switzerland, 4Institute of the Physics of Biological Systems, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

In vivo 1H MRS at high fields is a powerful tool able to assess the concentration of about 20 metabolites implicated in different cellular functions. Longitudinal studies on cerebral diseases involving modifications in the metabolites concentrations are routinely applied given the non invasiveness of the technique. The present study examines changes in the neurochemical profile after injection of the highly invasive human glioma derived sphere lines. Our results suggest that longitudinal comparison of modifications in the metabolic profiles of different brain regions allows studying the kinetics of tumor invasion

11:12 0528.   Breast cancer cells can be rescued by Matrigel from the growth inhibitory effects of HIF-1α and HIF-2α silencing
Santosh Kumar Bharti1, Balaji Krishnamachary1, Wenlian Zhu1, Flonne Wildes1, Samata M Kakkad1, Yelena Mironchik1, Dmitri Artemov1, and Zaver M Bhujwalla1
1Div. of Cancer Imaging Research, The Russell H. Morgan Dept. of Radiology and Radiological science, Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States

The heterodimeric transcription factors HIF-1/2 play an important role in driving angiogenesis by increasing the expression of vascular endothelial growth factor (VEGF) in hypoxic tumor microenvironments. Here we genetically modified the aggressive breast cancer cell line MDA-MB-231 to expresses short hairpin RNA that silences both isoforms of HIF (HIF-1α and HIF-2α). We found increased vascular permeability in HIF-1 and 2α silenced tumors compared to empty vector tumors, together with a growth advantage in the presence of Matrigel co-inoculated in the mammary fat pad. These data demonstrate the importance of the extracellular matrix in modulating outcomes of molecular pathway modifications.

11:24 0529.   Selective acidification and de-energization of WM983B melanoma xenografts and sensitization to doxorubicin following lonidamine administration
Kavindra Nath1, David S Nelson1, Daniel F Heitjan1, Rong Zhou1, Dennis B Leeper2, and Jerry D Glickson1
1University of Pennsylvania, Philadelphia, Pennsylvania, United States, 2Thomas Jefferson University, Pennsylvania, United States

Synopsis: WM983B melanoma xenografts exhibit a significant selective decrease in their intracellular pH following treatment with 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. Energetics is further attenuated by inhibition of electron transport, but the site of inhibition is not as well understood. 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 WM983B melanomas with doxorubicin following tumor acidification with LND demonstrates the potential clinical utility of combining LND with doxorubicin in the treatment of melanoma and other human cancers.

11:36 0530.   Hyperpolarizied 13C MRSI is a better predictor of survival than tumor size in treated glioblastoma
Marina Radoul1, Myriam M. Chaumeil1, Pia Eriksson1, and Sabrina M. Ronen1
1Radiology and Biomedical Imaging, UCSF, San Francisco, CA, United States

Resistance to current therapy and recurrence is not only common in glioblastoma but also expected. PI3K/Akt/mTOR signaling pathway, activated in most glioblastoma, represents an important target in alternative therapeutic approach. In order to prepare for an upcoming clinical trial, the goal of this study was to expand upon previous studies, and to confirm reproducibility in different model systems and genetic background, and with a novel PI3K/Akt/mTOR inhibitor. We used hyperpolarized 13C MRSI, and 1H MRS, and to monitor the effect of the dual PI3K/mTOR inhibitor XL765 (SAR245409) and TMZ alone or in combination in GS-2 tumors in mice.

11:48 0531.   
In vivo 19F MRI to Study ERK1 as a Target for Dendritic Cell Migration in High Grade Glioma
Min-Chi Ku1, Helmar Waiczies2, Andreas Pohlmann1, Susanne Wolf3, Helmut Kettenmann3, Sonia Waiczies1, and Thoralf Niendorf1
1Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrück Center for Molecular Medicine, Berlin, Germany, 2MRI.TOOLS GmbH, Berlin, Germany, Berlin, Germany, 3Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany

Immunotherapy with dendritic cell (DC)-based vaccines for treating glioma shed light in the treatment of brain tumors. To access the efficiency of DC vaccine, it is necessary to monitor the migration of DCs in the CNS or lymphoid organs. Our goal is to target molecules, which are involved in regulating DC migration within the glioma. In this study we showed that 19F/1H MRI can monitor the migration of DCs and identified ERK1 as a factor involved in DC migration.