Kannie Wai Yan Chan¹, Michael C McMahon^2,3, Guanshu Liu^4,5, Yoshinori Kato⁴, Zaver Bhujwalla⁴, Dmitri Artemov⁴, and Peter Christiaan van Zijl^1,5
1Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States, ²Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, ³F.M. Kirby Research Center, Kennedy Krieger Research Insitute, Baltimore, MD, United States, ⁴Johns Hopkins University School of Medicine, ⁵kennedy Krieger Research Insitute

PET studies of 18-fluorodeoxyglucose (18FDG) uptake can detect abnormal glucose uptake in tumors, which is an important biomarker for staging of cancer and assessing the efficacy of therapies. Using xenografts of a highly aggressive and metastatic human breast cancer cell line (MDA-MB-231) in mice, we show that glucose uptake can be imaged using non-labeled D-glucose intra-venous infusion through detection with chemical exchange saturation transfer (CEST). Magnetization transfer ratio asymmetry spectra showed a typical glucose line shape appearance. Glucose uptake reflects the combined effects of perfusion, leakage into extravascular extracellular space (EES), and metabolism.

Galia Tsarfaty¹, Ilan Tsarfaty², Sari Natan², Eli Konen¹, and Tammar Kushnir^1
1Dept. of Diagnostic Imaging, MRI Unit, The Chaim Sheba Medical Center, Tel Hashomer, Israel, ²Department of Human Microbiology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Met tyrosine kinase receptor and its ligand hepatocyte growth factor/scatter factor (HGF/SF) play an important role in a variety of human cancers. HGF/SF induce diverse metabolic alteration including increase in calcium intake to the tumor cells. MEMRI enables monitoring functional cellular Ca+2 intake, via in-vivo mapping of Mn+2 ions that enter the cells due to the permeability of voltage-gated calcium channels. Using MEMRI we demonstrate that HGF/SF enhances intake of Mn+2 to Met-dependent murine mammary tumors that is inhibited by the Ca+2 blocker Verapamil. Thus HGF/SF MEMRI may serve as a Met functional molecular imaging modality for monitoring anti-Met treatment.

Julie Magat¹, Elif Ozel¹, Valérie Marchand¹, Caroline Bouzin², Olivier Feron², Benedicte F Jordan¹, and Bernard Gallez^1
1Louvain Drug Research Institute, Biomedical Magnetic Resonance Research Group, University of Louvain, Brussels, B, Belgium, ²Pole of Pharmacotherapy, University of Louvain, Brussels, Belgium

Dissolved oxygen acts as a T1-shortening paramagnetic contrast agent. We suggest here to monitor the changes in R1 of the lipid peak instead of water to exploit the higher solubility property of oxygen in lipids. For this purpose, we developed a method to map variations in oxygenation based on the changes in the relaxation properties of the tissue lipids. The method was applied in vitro for calibration and in vivo lipids in vivo in mammary cancer models during breathing challenges. The measurement of R1 in lipids offer an increased sensitivity compared to previously described techniques that measure the variations of R1 in the water component

Inna V Linnik^1,2, Marietta Scott³, Neil Woodhouse³, John C Waterton^1,3, Helen Young³, Carsten Liess³, Hervé Barjat³, Jose Ulloa³, Cassandra L Hodgkinson⁴, Timothy Ward⁴, Caroline Dive⁴, Darren Roberts⁴, Josephine H Naish^1,2, and Geoffrey J M Parker^1,2
1Imaging Science and Biomedical Engineering, School of Cancer and Enabling Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom,²Biomedical Imaging Institute, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom, ³Imaging, Translational Sciences, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom, ⁴Paterson Institute for Cancer Research, Manchester, United Kingdom

Dynamic oxygen-enhanced (OE) MRI monitors the tissue change in longitudinal relaxation rate (R₁) when switching from breathing air to 100 % O₂. It was shown using dynamic OE-MRI that some tumour regions demonstrate an R₁ increase under O₂ inhalation consistent with the delivery of paramagnetic molecular oxygen via the blood plasma. However, our recent studies have demonstrated that tumours also exhibit regions that paradoxically reduce R₁ with the switch to O₂. Here we provide a theoretical explanation of this difference in response between regions and demonstrate that OE-MRI may provide a new non-invasive method for quantifying hypoxic extent in tumours.

Else Marie Huuse¹, Siver Andre Moestue¹, Tone Frost Bathen ¹, Anna Bofin², Gunhild Mari Mælandsmo³, Lars A Akslen⁴, Olav Engebraaten^3,5, and Ingrid S Gribbestad^1
1Department of Circulation and Medical Imaging, Norwegian University of Science and Tehcnology (NTNU), Trondheim, Norway, ²Department of Laboratory Medicine, Children's and Women's Health, NTNU, Trondheim, Norway, ³Department of Oncology and Department of Tumor Biology, Oslo University Hospital, Oslo, Norway, ⁴The Gade Institute, Section for Pathology, University of Bergen, Bergen, Norway, ⁵Institute for Clinical Medicine, University of Oslo, Oslo, Norway

Two new breast cancer xenograft models, reflecting luminal-like (MAS98.06, ER+, low growth rate) and basal-like (MAS98.12, ER-, high growth rate) subgroups, have recently been established by direct transplantation of primary tumor tissue. The differences in tumor vasculature and angiogenesis, and the effect of tumor volume were investigated using DCE-MRI and histopathological measures. The results showed a significantly higher Ktrans, vp and vascular proliferation index in the aggressive basal-like tumors compared to the luminal-like tumors. Additionally, the results showed a positive correlation between vp and micro vessel density and a negative correlation between vp and hypoxia and between Ktrans and hypoxia.

Shelby Katherine Wyatt¹, Sharon E Ungersma¹, Jason R Oeh², Calvin Ho¹, Tim C Cao¹, Hartmut Koeppen³, Lori S Friedman², Deepak Sampath², and Richard A. D. Carano^1
1Biomedical Imaging, Genentech, Inc, South San Francisco, CA, United States, ²Translational Oncology, Genentech, Inc, South San Francisco, CA, United States,³Pathology, Genentech, Inc, South San Francisco, CA, United States

This study aims to elucidate the role of PI3K and mTOR inhibition on vascular structure using an in-vivo multispectral vessel size index (VSI) MRI approach and ex-vivo micro-computed tomography (micro-CT) angiography. In-vivo multispectral VSI MRI demonstrated significant tumor growth suppression, reduced Q, increased VSI and decreased blood volume, while ex-vivo micro-CT angiography demonstrated decreased vascular density following PI3K/mTOR inhibition. These results are consistent with the loss of small vessels and help elucidate the effects of inhibiting the PI3K and mTOR pathways on vascular structure.

Norbert W. Lutz¹, Johanna Chiche², Yann LeFur¹, Frederic Frassineti³, Laurent Daniel³, Jacques Pouyssegur², and Patrick J. Cozzone^1
1Dept. of Medicine La Timone, Marseille, France, ²Institute of Developmental Biology and Cancer, University of Nice, Nice, France, ³Dept. of Pathology La Timone, Marseille, France

The excessive production of lactic acid through glycolysis in tumors can in principle be exploited for cancer treatment by using drugs to decrease intracellular pH (pH_i), thus inducing cell death. We now present results obtained for fibroblasts genetically manipulated to modulate two proton transport mechanisms, the sodium/proton exchanger, NHE1, and the monocarboxylate transporter, MCT4. pH_i and extracellular pH (pH_e) were determined simultaneously in vivo in a nude mouse model, in conjunction with tumor morphology, tumor growth and necrosis, and were complemented with histological data. Our results validate the suggested treatment concept based on manipulating pH regulation via MCT4 and NHE1.

Dania Daye¹, James Alvarez^2,3, Suzanne Wehrli⁴, Mitchell Schnall⁵, and Lewis Chodosh^2,3
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States, ²Department of Cancer Biology, University of Pennsylvania, ³Abramson Family Cancer Research Institute, University of Pennsylvania, ⁴Nuclear Magnetic Resonance Core Facility, Children's Hospital of Philadelphia, ⁵Department of Radiology, University of Pennsylvania

Breast cancer is the most commonly diagnosed malignancy in women and is the second leading cause of cancer-related death in the female population worldwide. Cancer recurrence represents the principal cause of death from this disease. To dissect the mechanisms implicated in recurrence, our lab has developed an inducible transgenic mouse model that accurately reproduces key features of the natural history of human breast cancer progression: primary tumor development, tumor dormancy and recurrence. The goal of this study was to investigate the role of 1H MRS metabolic profiling as a potential breast cancer progression marker using this model.

Rossella Canese¹, Giorgia Nardo², Marika Crescenzi², Egidio Iorio¹, and Stefano Indraccolo^2
1Istituto Superiore di Sanità, Rome, RM, Italy, ²Istituto Oncologico Veneto -IRCCS, Padova, Italy

We investigate by in vitro and in vivo 1H MRS two experimental models of ovarian cancer with different glycolytic phenotypes based on measurements of glucose consumption and lactate production rates in vitro as well as assessment of expression levels of glycolysis-associated genes. Metabolic differences have been detected between the two cell lines as well as the two in vivo models, notably in the lactate content. These differences were associated with tumour morphology and internal composition detected by MRI and ADC. These results could highlight a link between the Warburg effect and the response to anti angiogenic therapy in ovarian cancer.

Marie-France Penet¹, Kristine Glunde¹, Dmitri Artemov¹, Franca Podo², and Zaver M. Bhujwalla^1
1JHU ICMIC Program, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States,²Department of Cell Biology and Neurosciences, Section of Molecular and Cellular Imaging, Istituto Superiore di Sanità, Rome, Italy

Epithelial ovarian cancer remains the leading cause of death from gynecologic malignancy among women in developed countries. New therapeutic strategies evaluated with relevant preclinical models are urgently needed to improve survival rates. Here we have characterized orthotopically implanted ovarian tumors with in vivo MRI and MR spectroscopic imaging (MRSI), with the ultimate purpose of determining the effects of choline kinase targeting on tumor growth, metastasis occurrence, and ascites formation. Total choline and phosphocholine were significantly higher in orthotopic compared to subcutaneous tumors, demonstrating the importance of the inoculation site in the metabolic phenotype.