Preclinical & Human Studies of Tumor Therapy Response
Wednesday 22 April 2009
Room 315 10:30-12:30


Kristine Glunde and N. R. Jagannathan

10:30  409. Edema Control by Anti-VEGF Therapy Prolongs Survival Despite Persistent Tumor Growth in Mice
    Christian T. Farrar1, Walid Kamoun2, Carsten D. Ley2, Young R. Kim1, Guangping Dai1, Bruce R. Rosen1, Rakesh K. Jain2, A. Gregory Sorensen1
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA; 2Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA
    Recent clinical trials of anti-vascular endothelial growth factor (VEGF) agents for glioblastoma showed promising progression-free and overall survival rates. However, it is unclear whether this is due to anti-tumor or anti-edema effects of these agents. Thus the mechanisms leading to improved survival in patients remain unclear. Our goal was to determine whether alleviation of edema by anti-VEGF agents alone, without affecting tumor growth, could increase survival in mice. Here we examine in detail the impact of cediranib treatment on tumor growth, tumor blood volume, vessel caliber, edema, and permeability in a U87 mouse brain tumor model. In addition, we validate the MRI biomarkers of tumor angiogenesis with histology, optical microscopy, and wet-dry weight measurement methods.
10:42 410. Noninvasive Therapeutic Evaluation on Rodent Liver Tumor Treated with Vascular Disrupting Agent: Multiparametric Magnetic Resonance Imaging in Correlation with Microangiography and Histology
    Huaijun Wang1, Junjie Li1, Feng Chen1, Yicheng Ni1
Catholic University of Leuven, Leuven, East Flanders, Belgium
    This study aimed to document tumoricidal events after a vascular targeting agent ZD6126 in rodent liver tumors with clinical MRI in correlation with postmortem microangiography and histopathology. Rhabdomyosarcomas in rat liver were treated with i.v. injection of ZD6126. Therapeutic outcomes were evaluated morphologically and functionally with 1.5T MRI. Diffusion-weighted imaging and dynamic contrast-enhanced MRI successfully monitored vascular shutdown by ZD6126 at 1h after treatment, prior to the advent of morphological change of tumor size at 48h, which were verified with microangiography and histopathology. Clinical MRI allowed monitoring of ZD6126-related vascular shutdown, necrosis, and neovascularization of liver tumors in rats.
10:54 411. Vessel Size Index MRI for Evaluating the Effects of Multiple Anti-Angiogenic Therapies in Sequence
    Sharon E. Ungersma1, Glenn Pacheco2, Anil Bagri1, Shang-Fan Yu2, Andrew Mcgeehan2, Sarajane Ross2, Richard A.D. Carano1
Tumor Biology & Angiogenesis, Genentech, South San Francisco, CA, USA; 2Translational Oncology, Genentech, South San Francisco, CA, USA
    In vivo imaging of tumors treated with anti-angiogenic agents can reveal information about therapeutic effects on tumor vasculature. Vessel size index (VSI) MRI uses a USPIO contrast agent to determine the blood volume, mean vessel size, and Q (a parameter related to vessel density) for each voxel. We used VSI MRI to examine the effects of two potential therapies in sequence: anti-VEGF, an antibody to vascular endothelial growth factor, and anti-NRP1B, an anti-angiogenic agent believed to inhibit vessel maturation. The VSI technique detected significant reductions in vascular parameters that indicated an advantage to dosing with anti-NRP1B before anti-VEGF.
11:06 412. Assessment of Vascular Remodelling During Antiangiogenic Tumor Therapy Using DCE-MRI and Vessel Size Imaging
    Stefan Zwick1, Ralph Strecker2, Moritz Palmowski3, Peter Gall4, Valerij Kiselev4, Arne Hengerer2, Wolfhard Semmler1, Fabian Kiessling3
Medical Physics in Radiology, German Cancer Research Center, Heidelberg, Germany; 2HealthCare Sector, Siemens AG, Erlangen, Germany; 3Department of Experimental Molecular Imaging, RWTH-Aachen University, Aachen, Germany; 4Department of Diagnostic Radiology, University Hospital Freiburg, Freiburg, Germany
    To assess vascular remodelling in tumors during antiangiogenic therapy DCE-MRI and vessel size imaging were performed. Tumor bearing nude mice were treated with a multitargeted tyrosine kinase inhibitor and investigated before and after treatment. The decrease of A and increase of kep in treated compared to untreated tumors clearly showed therapy response. The mean vessel size measured by vessel size imaging significantly increased in treated as compared to untreated tumors. Results of both methods are in excellent agreement with histology. Thus, DCE-MRI and vessel size imaging were able to assess vascular remodelling during antiangiogenic tumor therapy.
11:18 413. Measurement of the Increase in Vessel Size Induced by a Vascular Disrupting Agent in Orthotopic Prostate Tumours Using Vessel Size Imaging
    Simon Walker-Samuel1, Jessica K. Boult1, Lesley D. McPhail1, Simon P. Robinson1
Cancer Research UK Clinical Magnetic Resonance Research Group, Institute of Cancer Research, Sutton, Surrey, UK
    In this study, susceptibility MRI with ultra-small paramagnetic iron oxide (USPIO) was used to estimate the vessel size index (VSI) in orthotopic PC3 prostate tumours following treatment with ZD6126, a vascular disrupting agent. It was found that orthotopic tumours exhibited larger vessels than typically found in ectopic (subcutaneous) tumour xenograft models (VSI = 65▒25ým), and that this significantly increased following treatment with ZD6126 (post-treatment VSI = 122▒36ým, p<0.05). An excellent correspondence was found with histological measurements of vessel size. This study highlights the potential use of VSI as a biomarker for assessing vascular architecture and response to vascular disrupting agents.
11:30 414. Can DCE MRI Predict Risk of Treatment Failure in Early-Stage Favorable-Prognosis Cervical Cancer Patients?
    Nina A. Mayr1, William T.C. Yuh2, Hualin Zhang1, Lanchun Lu1, Joe F. Montebello1, Steffen Sammet2, Guang Jia2, Jeffrey M. Fowler3, Kyle Porter4, David Jarjoura4, Jian Z. Wang1
Radiation, The Ohio State University, Columbus, OH, USA; 2Radiology, The Ohio State University, Columbus, OH, USA; 3Obstetrics & Gynecology, The Ohio State University, Columbus, OH, USA; 4Biostatistics, The Ohio State University, Columbus, OH, USA
    Despite favorable prognosis, many low risk cervical cancer patients ultimately fail therapy. The purpose of this study was to assess, if DCE MRI can predict poor treatment outcome in patients with otherwise favorable clinical prognosis judged by gold-standard clinical criteria. DCE MRI predicts treatment failure early in otherwise favorable-prognosis cervical cancer patients and provides a therapeutic window to modify the treatment strategies that can have profound impact to the long term outcome. This predictive ability is likely related to DCE MRIĺs ability to indentify and analyze the subregions of the heterogeneous tumor that likely represent tumor cells resistant to treatment.
11:42 415. Combining DCE-MRI and Microbubble Ultrasound to Evaluate Response to Sunitinib in Patients with Renal Cell Carcinoma
    Colleen Bailey1,2, Ross Williams2, Gord Lueck2, Mostafa Atri3, Peter N. Burns1,2, Greg J. Stanisz1,2, Georg A. Bjarnason4
Medical Biophysics, University of Toronto, Toronto, ON, Canada; 2Imaging Research, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; 3Medical Imaging, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; 4Medical Oncology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
    Patients with renal cell carcinoma were treated with the drug Sunitinib and examined by DCE-MRI and contrast-enhanced ultrasound. DCE-MRI provided the volume transfer constant, Ktrans, and the extravascular extracellular volume fraction ve. Disruption-replenishment provided the relative blood volume change. Combining the information from both imaging techniques provides a fuller picture of the tumour response to treatment.
11:54 416. Potential of Choline SNR, Tumor Volume and Diameter in the Assessment of Response of Locally Advanced Breast Cancer Patients Using Sequential MRSI and MRI
    Karikanni Kalathil A. Danishad1, Uma Sharma1, Rani Gupta Sah1, Vurthaluru Seenu2, Rajinder Parshad2, Naranamangalam R. Jagannathan1
Department of NMR and MRI Facility, All India Institute of Medcial Sciences, New Delhi, Delhi, India; 2Department of Sugical Disciplines, All India Institute of Medcial Sciences, New Delhi, Delhi, India
    Sequential MRSI [before therapy and after I, II and neo-adjuvant chemotherapy (NACT)] was carried out in 30 breast cancer patients to evaluate the potential of signal-to-noise ratio of choline (ChoSNR), tumor volume and diameter to predict tumor response. Changes in these parameters revealed significant decrease in ChoSNR after I NACT compared to pre-therapy in responders than non-responders. Sensitivity to detect responders using ChoSNR was 85.7% with 91% specificity while 100% sensitivity for volume and diameter but with reduced specificity (73% and 81.8%). When all the three parameters were combined, 100%sensitivity, 82% specificity with 87.5% PPV and 100% NPV was achieved.
12:06 417. Choline Metabolites as Biomarkers for Predicting Response to Neoadjuvant Chemotherapy in Local Advanced Breast Cancer Patients
    Maria Dung Cao1, Beathe Sitter1, Tone Frost Bathen1, Per E. L°nning2,3, Steinar Lundgren1,4, Ingrid Susann Gribbestad1
Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; 2Department of Oncology, Haukeland University Hospital, Bergen, Norway; 3University of Bergen, Bergen, Norway; 4Department of Oncology, St.Olavs University Hospital, Trondheim, Norway
    The presence and change in the composite choline signal detected in MR spectra has been suggested as a biomarker for breast cancer diagnosis and treatment monitoring. The purpose of this study was to evaluate quantitative changes in the level and composition of the choline-containing metabolites (tCho) prior to and after treatment with doxorubicin monotherapy in 30 patients with breast cancer. Our study suggests that quantitative changes in different choline profiles may be related to breast cancer treatment response.
12:18 418. Noninvasive Detection of Carboxypeptidase G2 Activity in Vivo using 19F 3D CSI
    Yann Jamin1, Lynette Smyth1, Simon P. Robinson1, Thomas R. Eykyn1, Caroline J. Springer1, Martin O. Leach1, Geoffrey S. Payne1
Institute of Cancer Research and Royal Marsden NHS trust, Sutton, UK
    Carboxypeptidase G2 (CPG2) is a bacterial enzyme used in cancer chemotherapy to activate selectively non toxic prodrugs into potent cytotoxics in tumors. We demonstrate that 19F 3D CSI can be used in combination with a surface coil to monitor dynamically and quantitatively the CPG2-mediated conversion of the reporter probe 3,5-difluorobenzoyl-L-glutamic acid (3,5-DFBGlu) into 3,5-difluorobenzoic acid (3,5-DFBA). This method could provide important information on the level of CPG2 activity in patient undergoing CPG2-based therapy.