/project 7

C.-C. Glüer and S. Tiwari, Kiel

Hierarchical 3D imaging of altered osteogenic activity as biomarkers in bone metastases and multiple myeloma

Bone comprises multiple cell types interacting with each other during skeletal metastatic processes. In the first funding period, we established mouse models for in vivo imaging of bone metastases giving rise to osteolytic and osteosclerotic lesions. We developed and tested new imaging methods including
I) kinetic analyses of binding of a fluorescent bisphosphonate conjugate with uptake rates indicative of location-specific metabolic status,
II) a registration procedure for time lapse micro-CT which improves the long-term precision of bone mineral and microstructure measurements in vivo and can identify local regions of bone apposition or loss, and
III) correction procedures for the attenuation of optical signals in bone tissue. We also
IV) established a transgenic mouse strain with recombination of the osterix promoter, regulating expression of the fluorescent protein Katushka which thus labels progenitor cells, osteoblasts and stromal cells, and
V) show that a fluorescent conjugate of the Kiss1 peptide localizes to bone metastatic and multiple myeloma cells as well as neighboring mesenchymal stem cells (MSCs). Based on this armamentarium of imaging biomarkers for diagnostic and therapeutic targeting, and on additional methodological developments, we will test the hypothesis that hierarchical in vivo multimodal biomarker imaging, linking mesoscopic with microscopic methods, will allow for spatiotemporal characterization of metastatic disease severity and the effects of treatment.

Our specific aims for the second funding period comprise:

(I) the use of our osterix-Katushka transgenic mouse model to mesoscopically and microscopically monitor the dynamics of tumor-associated progenitor cells (Osx+-MSCs) and osteoblasts in vivo as potential biomarkers for bone metastatic disease progression and therapy effects,

(II) the optimization and validation of optical bisphosphonate conjugates for selective, rapid binding at sites of active osteosclerotic metastases, and

(III) the development of micro-CT and second harmonic generation imaging methods as biomarkers for multimodal assessment of metastasis severity in osteolytic, osteosclerotic and mixed lesions.

Successful establishment of hybrid micro-CT & multiphoton / near infrared fluorescent imaging will allow development of methods for in vivo imaging of bone metastases and multiple myeloma with biomarkers identified in SKELMET partner projects. With the studies outlined in this proposal we aim at progress in the preclinical development of imaging agents that have translational potential to target disease and for therapy control.
 

Prof. Dr. rer. nat. Claus-C. Glüer first began working on medical applications of X-ray, developing synchrotron-based techniques for coronary angiography. After 7 years of research as assistant and associate adjunct professor at the University of California, San Francisco, he became a Professor of Medical Physics in the Department of Diagnostic Radiology, University Hospital Schleswig-Holstein in Kiel, Germany, in 1995. His research is focused on the development of innovative parametric imaging techniques and their quantitative evaluation. Working in the field of osteoporosis for more than 20 years, he has contributed specifically to the development of bone densitometry, quantitative ultrasound, and high-resolution computed tomography approaches. He has coordinated several multicenter studies including OPUS, a European project on epidemiology and optimized diagnostic assessment of osteoporosis.

Dr. Sanjay Tiwari obtained his PhD in the haematology department at University College of London, UK and worked 4 years as a post-doctoral fellow at the Dana-Farber Cancer Institute at Harvard Medical School in Boston, MA, researching in the field of haematological diseases. Since 2006, he has been working as a Senior Scientist at the University Hospital in Kiel, holding a joint position at the Institute of Tumor Research and Molecular Imaging North Competence Center (MOIN CC). His research interest has focused on application of molecular imaging for improved understanding of disease processes, in particular bone metastases.



Project-related list of publications  

Campbell GM, Tiwari S, Hofbauer C, Picke AK, Rauner M, Huber G, Peña JA, Damm T, Barkmann R, Morlock MM, Hofbauer LC, Glüer CC. Effects of parathyroid hormone  on cortical porosity, non-enzymatic glycation and bone tissue mechanics in rats with type 2 diabetes mellitus. Bone. 2016;82:116-21. 
 
Fritsche H, Heilmann T, Tower RJ, Hauser C, von Au A, El-Sheikh D, Campbell GM, Alp G, Schewe D, Hübner S, Tiwari S, Kownatzki D, Boretius S, Adam D, Jonat W, Becker T, Glüer CC, Zöller M, Kalthoff H, Schem C, Trauzold A. TRAIL-R2 promotes skeletal metastasis in a breast cancer xenograft mouse model. Oncotarget. 2015;6:9502-16.

Tower RJ, Campbell GM, Müller M, Glüer CC, Tiwari S. Utilizing time-lapse micro-CT-correlated bisphosphonate binding kinetics and soft tissue-derived input functions to differentiate site-specific changes in bone metabolism in vivo. Bone. 2015;74:171-81. 

Tower RJ, Campbell GM, Müller M, Will O, Glüer CC, Tiwari S. Binding kinetics of a fluorescently-labeled bisphosphonate as a tool for dynamic monitoring of bone mineral deposition in vivo. J Bone Miner Res 2014;29:1993-2003.

Hamann C, Picke AK, Campbell GM, Balyura M, Rauner M, Bernhardt R, Huber G, Morlock MM, Günther KP, Bornstein SR, Glüer CC, Ludwig B, Hofbauer LC. Effects of parathyroid hormone on bone mass, bone strength, and bone regeneration in male rats with type 2 diabetes mellitus. Endocrinology 2014;Jan 27:en20131960.

Campbell GM, Tiwari S, Grundmann F, Purcz N, Schem C, Glüer CC. Three-dimensional image registration improves the sensitivity to detect anabolic and catabolic changes in the bone mineral and microstructure of mice using micro-CT. Calcif Tissue Int 2014;94:282-92.

Ranta TM, Suojanen J, Peñate-Medina O, Will O, Tower RJ, Glüer C, Kairemo K, Gahmberg CG, Koivunen E, Sorsa T, Saris PE, Reunanen J. In vivo targeting of activated leukocytes by a β2-integrin binding peptide. Mol Diagn Ther 2014;18:39-44.

Schem C, Bauerschlag D, Bender S, Lorenzen AC, Loermann D, Hamann S, Rösel F, Kalthoff H, Glüer CC, Jonat W, Tiwari S. Preclinical evaluation of Sunitinib as a single agent in the prophylactic setting in a mouse model of bone metastases. BMC Cancer. 2013;13:32.

Tiwari S, Schem C, Lorenzen AC, Kayser O, Wiese C, Graeff C, Peña J, Marshall RP, Heller M, Kalthoff H, Jonat W, Glüer CC. Application of ex vivo micro-computed tomography for assessment of in vivo fluorescence and plain radiographic imaging for monitoring bone metastases and osteolytic lesions. J Bone Miner Metab 2012;30:373-80.

Campbell GM, Bernhardt, R, Scharnweber D, Boyd SK. The bone architecture is enhanced with combined PTH and alendronate treatment compared to monotherapy while maintaining the state of surface mineralization in the OVX rat. Bone 2011;49: 225-32.

Campbell GM, Ominsky MS, Boyd SK. Bone Quality is Partially Recovered after the Discontinuation of RANKL Administration in Rats by Increased Bone Mass on Existing Trabeculae: An in vivo micro-CT Study. Osteoporos Int 2011;22:931-42.

Meincke M, Tiwari S, Hattermann K, Kalthoff H, Mentlein R. Near-infrared molecular imaging of tumors via chemokine receptors CXCR4 and CXCR7. Clin Exp Metastasis 2011;28:713-20.

Tiwari S, Egberts JH, Korniienko O, Köhler L, Trauzold A, Glüer CC, Kalthoff H. Assessment of anti-inflammatory tumor treatment efficacy by longitudinal monitoring employing sonographic micro morphology in a preclinical mouse model. BMC Med Imaging 2011;11:15.

von Forstner C, Zuhayra M, Ammerpohl O, Zhao Y, Tiwari S, Jansen O, Kalthoff H, Henze E, Egberts JH. Expression of L amino acid transport system 1 and analysis of iodine-123-methyltyrosine tumor uptake in a pancreatic xenotransplantation model using fused high-resolution-micro-SPECT-MRI. Hepatobiliary Pancreat Dis Int 2011;10:30-7.

Krebs A, Graeff C, Frieling I, Kurz B, Timm W, Engelke K, Glüer CC. High resolution computed tomography of the vertebrae yields accurate information on trabecular distances if processed by 3D fuzzy segmentation approaches. Bone 2009;44:145-152.

Glüer CC, Schem C, Tiwari S, Heller M, Jonat W. Molekulare Bildgebung in der gynäkologischen Onkologie. Gynäkologe 2009;42:859-864.

Meincke M, Schlorf T, Kossel E, Jansen O, Glüer CC, Mentlein R. Iron oxide-loaded liposomes for MR imaging. Front Biosci 2008;13:4002-4008.

Graeff C, Timm W, Nickelsen TN, Farrerons J, Marin F, Barker C, Glüer CC. Monitoring teriparatide-associated changes in vertebral microstructure by high-resolution CT in vivo: results from the EUROFORS study. J Bone Miner Res 2007;22:1426-1433.

Glüer CC, Barkmann R, Hahn HK, Majumdar S, Eckstein F, Nickelsen TN, Bolte H, Dicken V, Heller M. Parametric biomedical imaging--what defines the quality of quantitative radiological approaches? Röfo 2006;178:1187-1201.

Tiwari S, Dong H, Kim EJ, Weintraub L, Epstein PM, Lerner A. Type 4 cAMP phosphodiesterase (PDE4) inhibitors augment glucocorticoid-mediated apoptosis in B cell chronic lymphocytic leukemia (B-CLL) in the absence of exogenous adenylyl cyclase stimulation. Biochem Pharmacol 2005;69:473-483.

Tiwari S, Felekkis K, Moon EY, Flies A, Sherr DH, Lerner A. Among circulating hematopoietic cells, B-CLL uniquely expresses functional EPAC1, but EPAC1-mediated Rap1 activation does not account for PDE4 inhibitor-induced apoptosis. Blood 2004;103:2661-2667.

Tiwari S, Italiano JE, Jr., Barral DC, Mules EH, Novak EK, Swank RT, Seabra MC, Shivdasani RA. A role for Rab27b in NF-E2-dependent pathways of platelet formation. Blood 2003;102:3970-3979.

Schwer HD, Lecine P, Tiwari S, Italiano JE, Jr., Hartwig JH, Shivdasani RA. A lineage-restricted and divergent beta-tubulin isoform is essential for the biogenesis, structure and function of blood platelets. Curr Biol 2001;11:579-586.
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