Joint Annual Meeting ISMRM-ESMRMB 2014 10-16 May 2014 Milan, Italy

Cancer Preclinical: Cells to Animals

Thursday 15 May 2014
Red 1 & 2  13:30 - 15:30 Moderators: Maria D. Cao, Ph.D., E. Jim Delikatny, Ph.D.

13:30 0842.   Hypoxia and HIF silencing dysregulates total choline, CD44 expression, and metastatic burden in MDA-MB-231 human breast cancers
Balaji Krishnamachary1, Santosh Kumar Bharti1, Marie-France Pennet1, Samata M Kakkad1, Flonne Wildes1, Keve Zoltani1, Yelena Mironchik1, and Zaver M Bhujwalla1
1Radiology, Johns Hopkins University, Baltimore, MD, United States

Hypoxic tumors frequently exhibit an aggressive phenotype due to dysregulated gene expression and metabolic changes. Cancers typically exhibit elevated phosphocholine mostly due to increased choline kinase expression and activity. Here we have established a relationship between hypoxia inducible factor (HIF) and choline distribution in vivo, and have shown that silencing both HIF-1α and HIF-2α reduces total choline and metastatic burden. We have identified a role for CD44, a breast cancer stem-like cell marker, in lung colonization

13:42 0843.   
In Vivo Monitoring of Caspase-3 Activity with MRI in Response to Different Treatment Modalities
Kimberly Brewer1, Adam J Shuhendler1, Deju Ye1, Prachi Pandit1, Magdalena Bazalova2, Edward Graves2, Jianghong Rao1, and Brian K Rutt1
1Radiology, Molecular Imaging Program, Stanford University, Stanford, California, United States, 2Radiation Oncology, Stanford University, Stanford, California, United States

Our group has previously reported on the development of a novel MRI caspase-3 activatable contrast agent based on intramolecular cyclization. Introduced into the system as small molecules, it cyclizes and self-assembles into Gd-nanoaggregates inside of target cells. We investigated caspase-3 activity (and thus apoptotic cells) in two different but common treatment modalities, chemotherapy and radiation therapy, that induce apoptosis in cancer cells. We found significant MRI signal enhancement for both sets of treated mice, each with distinct intratumoral localization. By studying the differences in caspase activity and localization we can explore the efficiency of these clinically relevant cancer treatments.

13:54 0844.   
Detection of Acute Response to Proteasome Inhibitor Treatment in Mouse Colorectal Tumour Models Using Amide Proton Transfer (APT) Magnetic Resonance Imaging
Yanan Zhu1, Rajiv Ramasawmy1, Sean Peter Johnson2, Valerie Taylor1, Barbara Pedley2, Allison Berger3, Nibedita Chattopadhyay3, Daniel Bradley4, Mark Lythgoe1, and Simon Walker-Samuel1
1UCL Centre for Advanced Biomedical Imaging, University College London, London, Greater London, United Kingdom, 2UCL Cancer Institute, University College London, Greater London, United Kingdom, 3Cancer Pharmacology Takeda Pharmaceutical International Corporation, MA, United States, 4The Biomedical Imaging Group, Takeda Pharmaceutical International Corporation, MA, United States

In this study, amide proton transfer (APT) imaging was used to assess the acute response of a colorectal xenograft model to proteosome inhibitor therapy (ixazomib). Tumour apparent diffusion coefficient (ADC), T1, and T2 were also acquired, alongside 31P magnetic resonance spectroscopy data. Treated mice showed an inhibited tumour growth rate, decreased APT and increased ADC, compared with control mice, which could be due to changes in protein homeostasis as a result of proteasome inhibition by the drug.

14:06 0845.   CEST-MRI detects metabolite levels for monitoring breast cancer cell aggressiveness - permission withheld
Kannie WY Chan1,2, Lu Jiang3, Jannie P Wijnen3, Guanshu Liu1,2, Tiffany Greenwood1, Menglin Chen1, Peter CM van Zijl1,2, Michael T McMahon1,2, and Kristine Glunde3,4
1Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States, 2Kennedy Krieger Institute, Baltimore, MD, United States,3Radiology, Division of Cancer Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, United States, 4Sidney Kimmel Comprehensive Cancer Center, MD, United States

Altered metabolism is a hallmark of cancer, and in vivo assessment of metabolite levels is important for cancer diagnosis, development of anti-cancer treatments, and treatment monitoring. In the in vivo setting, MR spectroscopic imaging (MRSI) is not able to spatially resolve some of the metabolites that are important in cancer due to their relatively low concentrations. Chemical Exchange Saturation Transfer (CEST) is a molecular imaging approach that can improve detection sensitivity. Here we applied CEST to detect exchangeable protons of common cellular metabolites, showing that the metabolite CEST contrast in breast cell lines is inversely correlated with cancer cell aggressiveness.

14:18 0846.   
Metabolic Changes in a Rat Glioma Model After Anti-Angiogenic Treatment Measured by MR Spectroscopic Imaging of Hyperpolarized [1-13C]Pyruvate
Jae Mo Park1, Sonal Josan1, Taichang Jang2, Milton Merchant2, Ralph Hurd3, Dirk Mayer4, Lawrence Recht2, and Daniel Spielman1
1Radiology, Stanford University, Stanford, CA, United States, 2Neurology and Neurological Sciences, Stanford University, Stanford, CA, United States,3GE Healthcare, CA, United States, 4Diagnostic Radiology and Nuclear Medicine, University of Maryland, MD, United States

We hypothesize that, in addition to changes in permeability, anti-VEGF drug also acutely and temporarily forces increased oxidative phosphorylation in glioma tissue due to nutrient depletion, increasing tumor vulnerability. Using an optimized 13C MRS imaging sequence, we were able to reproducibly image 13C-Bic in addition to 13C-Lac labeling using hyperpolarized [1-13C]Pyr in tumor-bearing rats, reflecting oxidative phosphorylation and glycolysis, respectively. After anti-VEGF treatment, Lac/Bic decreased significantly (at 3h post-treatment) and gradually increased back (24h and 48h post-treatment) in glioma while Lac/Bic did not have metabolic perturbation due to the drug. The increased Lac/Bic at 24h and 48h relatve to 3h suggests this might be a temporary phenomenon. We suggest that real time Bic measurements may provide both a useful biomarker for anti-angiogenic therapies and a potentially exploitable therapeutic strategy.

14:30 0847.   2-Hydroxyglutarate Labeling from [U-13C]glucose in Human Glioma Cells
Hyeon-Man Baek1,2, Yun-Ju Lee1, Gregory Hyung Jin Park1, Eun-Hee Kim1, and Chaejoon Cheong1,2
1Division of MR Research, Korea Basic Science Institute, Ochang, Chungbuk, Korea, 2Department of Bio-Analytical Science, University of Science & Technology, Yuseong-gu, Daejeon, Korea

We present here that the data analysis of 1H- and 13C-NMR spectra of the cell extracts showed a significant increase in the concentration of the 2HG in IDH mutated cells, but not in IDH wild type cells and mutant IDH cells with low transfection efficiency. In particular, 2HG-C5 labeling peaks from 13C-substrate were well separated from other metabolites (e.g., glutamate C-5 at 182.04, lactate C-1 at 183.23 ppm, etc.) in the 900MHz 1H-NMR spectra. This result demonstrates that 2HG can be actively being produced during the 24h period of [U-13C]glucose substrate feeding.

14:42 0848.   13C MRS detects TCA down-regulation in mutant IDH1 glioma cells
Jose Luis Izquierdo Garcia1, Pia Eriksson1, Cai Larry1, Myriam Chaumeil1, Russell O Pieper2, Joanna J Phillips2, and Sabrina M Ronen1
1Radiology, UCSF, San Francisco, CA, United States, 2Neurological Surgery, Helen Diller Research Center, UCSF, San Francisco, CA, United States

Mutations in Isocitrate dehydrogenase (IDH1) have been reported in over 70% of low-grade gliomas and secondary glioblastomas. In this study, the metabolism of live U87IDHmut and U87IDHwt cells was probed by thermally and Hyper-polarized (HP) 13C-MRS. HP-1,2-13C Piruvic Acid MRS showed a drop in 5-13C glutamate production and an increase in lactate and alanine production. 1-13C glucose infusion resulted in a drop of glutamate in U87IDHmut cells whereas glucose uptake was not significant difference. The increase in lactate and alanine and the decrease of glutamate production in U87IDHmut cells indicate that TCA down-regulation is a major effect of IDH mutation.

14:54 0849.   
Metabolic subgrouping of breast cancer using HR MAS MRS and hierarchical cluster analysis; correlation with molecular subtypes
Leslie R. Euceda1,2, Tonje H. Haukaas1,2, Guro F. Giskeødegård1, Marit Krohn2,3, Ellen Schlichting4, Rolf Kåresen2,4, Sandra Nyberg2,3, Kristine Kleivi Sahlberg2,3, Anne-Lise Børresen-Dale2,3, and Tone F. Bathen1,2
1Department of Circulation and Medical Imaging, Faculty of Medicine, NTNU, Trondheim, Norway, 2K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway, 3Department of Genetics, Institute for Cancer Research Oslo University Hospital, The Norwegian Radium Hospital, Norway, 4Department of Surgery, Oslo University Hospital, Ullevål, Oslo, Norway

Metabolic subgroups resulting from hierarchical clustering of MR metabolic profiles from a large cohort of breast tumor biopsies were combined with data from gene expression and reverse phased protein arrays to search for any relationship between metabolic profiles and molecular subtypes. No such relationships were established, which might make it possible for a more refined division of subtypes into subclasses based on metabolic differences. Bridging information from several molecular levels in the same tumor may improve our knowledge about various classes of breast cancer that may contribute to personalized treatment.

15:06 0850.   Metabolic characterization of triple negative breast cancer
Guro Fanneløb Giskeødegård1,2, Maria Dung Cao1,2, Santosh Lamichhane3, Beathe Sitter4, Anna Bofin5, Steinar Lundgren2, Hans Fjøsne2, and Tone Frost Bathen1
1Dept. of Circulation and Medical Imaging, NTNU, Trondheim, Norway, 2St. Olavs University Hospital, Trondheim, Norway, 3Department of Food Science, Aarhus University, Denmark, 4Sør-Trøndelag University College, Norway, 5NTNU, Trondheim, Norway

Triple negative breast cancer (TNBC), characterized by estrogen receptor (ER), progesterone receptor (PgR) and HER2 negativity, represents 15-20% of all breast cancer cases. TNBC is associated with more aggressive and higher grade tumors and poor prognosis. Current treatment options for TNCB are few and the responses are often insufficient. Novel molecular targets for the treatment of TNBC are needed to improve treatment care and survival of this breast cancer subgroup. The purpose of this study was to characterize metabolic differences between TNBC as compared to triple positive breast cancer and to identify potential molecular markers of TNBC tumors for targeted treatment.

15:18 0851.   Metabolite profiling and metabonomic approaches of fecal extracts from patients with chronic ulcerative colitis and colorectal cancer based on 9.4T NMR spectroscopy and pattern recognition
Yan Lin1, ChengKang Liu1, Zhiwei Shen1, and Renhua Wu1
1Radiology Department, Second Affiliated Hospital, Shantou University Medical College, Shantou City, Guangdong Province, China

This present study is a NMR-based metabolomics approaches coupled with pattern recognition methods to evaluate the ability to characterize the metabolic ¡°fingerprint¡± of fecal extracts from patients with ulcerative colitis (UC) and colorectal cancer (CRC). The most significant metabolites for classification include short-chain fatty acids, alanine, isoleucine, leucine, valine, glutamate, glycerol and the spectra in the aromatic region (6.6¨C8.2ppm), suggesting changes in the gut microbial community or malabsorption. This work shows the potential of MR-based metabolomics of fecal extracts in providing useful non-invasive diagnostic information for UC and CRC diseases and may further our understanding of colonic cancer mechanisms.