Cancer Preclinical: Animal Studies

Monday 12 May 2014

Igor Jacobs^1,2, Gustav Strijkers^1,2, Henk Keizer³, Henk Janssen³, Klaas Nicolay^1,2, and Matthias Schabel^4
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.

Marie-France Penet*¹, Tariq Shah*¹, Santosh Bharti¹, Yelena Mironchik¹, Flonné Wildes¹, Anirban Maitra², and Zaver M. Bhujwalla^1
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.

Min-Hui Cui^1,2, Ziqiang Yuan³, Sean Cahill⁴, Asha Adem³, Steven K. Libutti³, and Craig A. Branch^1,2
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.

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. Koutcher^1
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.

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 Robinson^2
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.

Florence Colliez¹, Marie-Aline Neveu¹, Julie Magat¹, Thanh Trang Cao Pham¹, Bernard Gallez¹, and Bénédicte F Jordan^1
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.

Kejia Cai^1,2, He N Xu¹, Anup Singh¹, Lily Moon¹, Mohammad Haris^1,3, Xiaohong Joe Zhou², Ravinder Reddy¹, and Lin Z Li^1
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.

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 Tedoldi^1
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.

Ilwoo Park¹, Rintaro Hashizume², Peder EZ Larson¹, C. David James², Daniel B Vigneron^1,3, and Sarah J Nelson^1,3
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.

Min-Chi Ku¹, Martin Günther¹, Conrad Martin¹, Stefano Lepore¹, Helmar Waiczies^1,2, Andreas Pohlmann¹, Susanne A. Wolf³, Helmut Kettenmann³, Thoralf Niendorf¹, and Sonia Waiczies^1
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.