Yan Lin¹, Changchun Ma², Zhiwei Shen¹, zhening wang¹, and Renhua Wu^1
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 ¡°fingerprint¡± 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.

Tariq Shah¹, Balaji Krishnamachary¹, Flonne Wildes¹, Jannie Wijnen², Kristine Glunde¹, and Zaver M Bhujwalla^1
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.

Sean P Arlauckas¹, Manoj Kumar¹, Anatoliy V Popov¹, Harish Poptani¹, and Edward J Delikatny^1
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.

Ailin Falkmo Hansen¹, Elise Sandsmark¹, Morten Beck Rye^2,3, Alan Wright⁴, Helena Bertilsson^2,5, Anna M. Bofin⁶, Anders Angelsen¹, Tone Frost Bathen¹, and May-Britt Tessem^1,3
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.

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 Ronen^1
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.

Mor Mishkovsky¹, Cristina Cudalbu², Irene Vassallo³, Marie-France Hamou³, Arnaud Comment⁴, Monika Hegi³, and Rolf Gruetter^1,2
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

Santosh Kumar Bharti¹, Balaji Krishnamachary¹, Wenlian Zhu¹, Flonne Wildes¹, Samata M Kakkad¹, Yelena Mironchik¹, Dmitri Artemov¹, and Zaver M Bhujwalla^1
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.

Kavindra Nath¹, David S Nelson¹, Daniel F Heitjan¹, Rong Zhou¹, Dennis B Leeper², and Jerry D Glickson^1
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.

Marina Radoul¹, Myriam M. Chaumeil¹, Pia Eriksson¹, and Sabrina M. Ronen^1
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.

Min-Chi Ku¹, Helmar Waiczies², Andreas Pohlmann¹, Susanne Wolf³, Helmut Kettenmann³, Sonia Waiczies¹, and Thoralf Niendorf^1
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.