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

Cancer Preclinical: Animal Studies

Monday 12 May 2014
Silver  10:45 - 12:45 Moderators: Tone F. Bathen, Ph.D., Kristine Glunde, Ph.D.

10:45 0042.   
A novel approach to tracer-kinetic modeling of (macromolecular) multi-bolus DCE-MRI data, applied in a murine tumor model
Igor Jacobs1,2, Gustav Strijkers1,2, Henk Keizer3, Henk Janssen3, Klaas Nicolay1,2, and Matthias Schabel4
1Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands, 2Center for Imaging Research and Education, Eindhoven, Netherlands, 3SyMO-Chem BV, Eindhoven, Netherlands, 4Advanced Imaging Research Center, Oregon Health and Science University, Portland, Oregon, United States

Conventional low-molecular-weight DCE-MRI and tracer-kinetic modeling does not support separate estimates of blood flow and microvascular permeability, while this would be advantageous for accurate cancer treatment evaluation. In this research a multi-bolus DCE-MRI protocol was developed, in which contrast agents of various molecular weights were injected sequentially. A novel tracer-kinetic modeling approach, based on the two-compartment exchange model, was applied to simultaneously fit multi-bolus data. The feasibility of this approach was shown in a murine tumor model. Single-pixel multi-bolus curves were of good quality and significant differences in extraction fraction and washout rate constant were observed between the different contrast agents.

10:57 0043.   Altered choline phospholipid metabolism in pancreatic cancer cells and tumor xenografts
Marie-France Penet*1, Tariq Shah*1, Santosh Bharti1, Yelena Mironchik1, Flonné Wildes1, Anirban Maitra2, and Zaver M. Bhujwalla1
1JHU ICMIC Program, Division of Cancer Imaging Research, The Johns Hopkins University School of Medicine, Baltimore, MD, United States, 2The University of Texas MD Anderson Cancer Center, Houston, TX, United States

Pancreatic cancer is an aggressive disease usually advanced at the time of diagnosis. Biomarkers with sensitivity and specificity for early diagnosis are urgently needed. Here we have investigated the metabolism of a panel of pancreatic cell lines in vitro and in vivo. Using high-resolution 1H MRS we observed elevated choline-containing compounds, along with high levels of choline kinase. Total choline signal was detected in vivo in tumor xenografts, with the highest concentration in the Panc1 tumors. Our study showed that the altered choline phospholipid metabolism could be used for noninvasive detection of pancreatic cancer and for treatment strategies.

11:09 0044.   In vivo 1H MRS detection of choline compounds in pancreas of MEN1 knock-out mice
Min-Hui Cui1,2, Ziqiang Yuan3, Sean Cahill4, Asha Adem3, Steven K. Libutti3, and Craig A. Branch1,2
1Gruss Magnetic Resonance Research Center, Albert Einstein College of Medicine, Bronx, New York, United States, 2Radiology, Albert Einstein College of Medicine, Bronx, New York, United States, 3Surgery, Albert Einstein College of Medicine, Bronx, New York, United States, 4Biochemistry, Albert Einstein College of Medicine, Bronx, New York, United States

We have demonstrated that in vivo 1H MRS has a potential role in diagnosis of pancreatic cancer, in a multiple endocrine neoplasia type 1 (MEN1) conditional knock-out mouse model. Choline was detected in Men1 KO mice via in vivo 1H MRS, but not in WT mice. The elevated total choline levels in Men1 KO mice were mainly due to high levels of phophocholine and glycerophosphocholine in pancreas tissues. Our approach may provide additional beneficial information in the context of pancreatic lesion diagnosis and allow monitoring tumor responsiveness to treatment.

11:21 0045.   Assessment of the Tumor Type-Specific Microenvironment – Lactate, Vascularity, Hypoxia, Extracellular pH
Ellen Ackerstaff1, Natalia Kruchevsky1, Ekaterina Moroz1, Nirilanto Ramamonjisoa1, Rui V. Simoes1, H. Carl LeKaye1, Kristen L. Zakian1, Hansol Lee2, HyungJoon Cho2, Radka Stoyanova3, Inna Serganova1, Ronald G. Blasberg1, and Jason A. Koutcher1
1Memorial Sloan-Kettering Cancer Center, New York, NY, United States, 2Ulsan National Institute of Science and Technology, Ulsan, Korea, 3Miller School of Medicine, University of Miami, Miami, FL, United States

A hostile tumor microenvironment impacts tumor growth, progression, metastases, and treatment resistance. More aggressive tumors have been associated with increased lactate production, acidity, and suppressed T-cell immune response. Here, we characterize noninvasively in vivo the tumor microenvironment in tumor models of different origin and aggressivity and investigate the relationship of lactate metabolism, vascularity, hypoxia, and extracellular pH (pHe) to tumor type / aggressivity, using 1H MRI/MRS/MRSI. Our data suggest that pHe does not directly relate to tumor lactate levels and that interplay of tumor metabolic activity and vascularization regulates tumoral pHe, showing the importance to assess these parameters independently.

11:33 0046.   Multiparametric MRI mapping of oxygen delivery and hypoxia in renal 786-O-R murine xenografts
James PB O'Connor1, Yann Jamin2, Jessica KR Boult2, Muhammad Babur3, John C Waterton1, Damien McHugh1, Andrew R Reynolds4, Kaye J Williams3, Geoff JM Parker1, and Simon P Robinson2
1Imaging Sciences, University of Manchester, Manchester, Greater Manchester, United Kingdom, 2Radiotherapy and Imaging, Institute of Cancer Research, Sutton, London, United Kingdom, 3School of Pharmacy, University of Manchester, Manchester, Greater Manchester, United Kingdom,4Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Sutton, London, United Kingdom

T1weighted oxygen-enhanced MRI can measure oxygen delivery and hypoxia in tumors. We report the first study to combine this method with BOLD, DCE-MRI and immunohistochemistry. We show how combining these modalities provides fresh insight into the spatial and temporal oxygen handling of 786-O-R renal xenografts.

11:45 0047.   
Is R1 of Lipids related to pO2? Lessons from two tumor models
Florence Colliez1, Marie-Aline Neveu1, Julie Magat1, Thanh Trang Cao Pham1, Bernard Gallez1, and Bénédicte F Jordan1
1Louvain Drug Research Institute, Biomedical Magnetic Resonance Research Group, University of Louvain, Brussels, Belgium

Variations in T1 and T2* are potentially valuable MRI tools to follow changes in tumor oxygenation. T2* is sensitive to the relative Hb/HbO2 ratio in vessel, while T1 change is sensitive to dissolved oxygen which acts as a T1-shortening paramagnetic contrast agent. The aim of the current work is to investigate the quantitative aspect of a new oxygen mapping method: MOBILE. Two tumor models were submitted to (i) hyperoxic challenges induced by carbogen breathing and (ii) hypoxic challenges induced by Combetastatin A-4 Phosphate. Actual pO2 values were obtained by EPR oximetry and significantly correlated to Lipids R1 values.

11:57 0048.   Noninvasive MRI of tissue redox state based on endogenous chemical exchange saturation transfer (CEST) contrast
Kejia Cai1,2, He N Xu1, Anup Singh1, Lily Moon1, Mohammad Haris1,3, Xiaohong Joe Zhou2, Ravinder Reddy1, and Lin Z Li1
1Radiology, University of Pennsylvania, Philadelphia, PA, United States, 2CMRR 3T Research Program, Radiology, University of Illinois at Chicago, Chicago, IL, United States, 3Sidra Medical and Research Center, Doha, Qatar

The disturbed balance of the redox state, such as excessive oxidative stress, can lead to many pathologic changes including cancer, heart diseases, neurodegenerative diseases, and diabetes. Imaging biomarkers for oxidative stress are a key research area. The purpose of this study is to develop a non-invasive MR imaging method for mapping the tissue redox state based on the endogenous Chemical Exchange Saturation Transfer (CEST) contrast. We report herein a CEST MRI technique, together with correlations to optical redox scanning to characterize tumor redox heterogeneity. The mechanism on such correlation has also been investigated.

12:09 0049.   Probing cancer metabolism with hyperpolarized 5-13C-glutamine
Claudia Cabella1, Magnus Karlsson2, Carolina Canapè3, Giuseppina Catanzaro1, Sonia Colombo Serra1, Luigi Miragoli1, Luisa Poggi1, Fulvio Uggeri1, Luca Venturi3, Pernille R. Jensen2, Mathilde H. Lerche2, and Fabio Tedoldi1
1CRB Bracco Imaging SpA, Colleretto Giacosa, Torino, Italy, 2Albeda Research Aps, Copenhagen, Denmark, 3University of Torino, Torino, Italy

Glutamine metabolism is a key marker of cancer development. In particular, strong correlations have been reported between oncogene expression and activity of the glutaminase enzyme. Hyperpolarized 13C-MR spectroscopy can provide insight to glutamine metabolism and should hence be a valuable tool to study changes in glutaminase activity as tumours progress. This work reports on an improved preparation of hyperpolarized 5-13C-glutamine, providing a highly sensitive MR marker. Physiological tolerable glutamine solutions with remarkable polarization levels were obtained by dissolution and used to perform 13C metabolic analysis in vivo in healthy and tumour bearing rats and for testing pharmacological treatments in vitro.

12:21 0050.   
Measuring Tumor Metabolism in Diffuse Intrinsic Pontine Gliomas (DIPG) Using Hyperpolarized Carbon-13 MR Spectroscopic Imaging
Ilwoo Park1, Rintaro Hashizume2, Peder EZ Larson1, C. David James2, Daniel B Vigneron1,3, and Sarah J Nelson1,3
1Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United States, 2Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, United States, 3Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, United States

Diffuse intrinsic pontine gliomas (DIPGs) are one of the most difficult pediatric cancers to treat. The methods for assessing treatment response and tumor progression are based on radiographic response but conventional MRI is not sufficient for predicting clinical outcome. We have demonstrated the feasibility of using hyperpolarized 13C metabolic imaging to evaluate in vivo metabolism in orthotopic brainstem xenografts injected with human DIPG cells. The results suggest that this technique may provide a unique non-invasive imaging tool that is able to differentiate between different tissue pathologies and aid in the management of patients with DIPG.

12:33 0051.   
19F MRI for Evaluating ERK1 as a Factor Regulating Dendritic Cell Migration in High Grade Glioma
Min-Chi Ku1, Martin Günther1, Conrad Martin1, Stefano Lepore1, Helmar Waiczies1,2, Andreas Pohlmann1, Susanne A. Wolf3, Helmut Kettenmann3, Thoralf Niendorf1, and Sonia Waiczies1
1Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrück Center for Molecular Medicine, Berlin, Germany, 2MRI.TOOLS GmbH, Berlin, Berlin, Germany,3Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany

Immunotherapy with dendritic cell based vaccines for treating glioma has become one attractive approach. To access the efficiency of DC vaccine, it is necessary to monitor the distribution of DCs in the CNS or lymphoid organs. Our goal is to target molecules, which are involved in regulating DCs within the glioma context. In this study we found that deficiency of ERK1 result in tumor regression. 19F/1H MRI monitored the migration of DCs and found that ERK1 can regulate DC migration.