Quantification of tumor characteristics with MRI for tumor characterization and therapy evaluation
Nuclear Medicine, Radiotherapy, Radiobiology
Final Report Abstract
In clinical routine, the effects of anti-tumor therapies are mostly analyzed by measuring the diameter on baseline and follow up cross sectional computed tomography or magnetic resonance imaging (MRI) scans, which can reliably assess the effects of classical cytotoxic chemotherapeutics. Targeted therapies are modern therapeutics designed to alter specific tumor traits like the vasculature or the surrounding immune cells. Effective anti-tumor treatment with these therapies often does not primarily reduce tumor size, and phenomena like intra-tumoral bleeding or fluid collections can even lead to an increase in size, called “pseudoprogression”. The aim of this project was to create dedicated MRI protocols to enable detailed assessment of tumor characteristics and their changes under therapy. In a first step, two different murine models of breast cancer were evaluated over time, with a comprehensive MRI protocol comprising the application of the albumin-binding contrast material gadofosveset. The results enabled to non-invasively differentiate between the low malignant 67NR and the high malignant 4T1 tumor model and characterize the tumor regarding intra-tumoral fluid distribution, heterogeneity and endothelial permeability. As preliminary experiments for assessment of therapeutic changes, specific alterations of the tumor vasculature and the tumor microenvironment (TME) were performed, using vesselstabilizing angiopoietin-1 and macrophage-depleting clodronate-loaded liposomes. Afterwards, the effects of two clinically approved therapeutic approaches were assessed, the multikinase inhibitor sorafenib, targeted against the tumor vasculature and a combination of two immune checkpoint inhibitors, to enhance their effects. A similar MRI examination to the beforementioned protocol enabled to assess treatment effects on the tumor vasculature of the respective treatments, revealing post-therapeutic changes in endothelial permeability, while an MRI examination without the need for contrast material injection revealed changes in intra-tumoral heterogeneity after targeted therapies. A different, specific MRI sequence enabled to non-invasively assess the mean cell size of the tissue. As macrophages are larger and T-cells smaller than tumor cells, changes of the intratumoral cell composition led to respective changes in mean cell size. Therefore, differences between the two tumor models of differing grades of malignancy and changes during progression were visible, as well as the T-cell infiltrate caused by immune checkpoint inhibition. As a last subproject, the metabolic profiling of tumors was assessed with chemical exchange saturation transfer MRI, which enables to evaluate changes in metabolites including glucose, APT and creatine without the need for radiation. These examinations not only revealed changes during tumor progression, with progressive necrosis in high malignant 4T1 tumors, but also therapy-related changes after immune checkpoint inhibition.
Publications
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Multiparametric MRI enables for differentiation of different degrees of malignancy in two murine models of breast cancer. Frontiers in Oncology, 12.
Gerwing, Mirjam; Hoffmann, Emily; Kronenberg, Katharina; Hansen, Uwe; Masthoff, Max; Helfen, Anne; Geyer, Christiane; Wachsmuth, Lydia; Höltke, Carsten; Maus, Bastian; Hoerr, Verena; Krähling, Tobias; Hiddeßen, Lena; Heindel, Walter; Karst, Uwe; Kimm, Melanie A.; Schinner, Regina; Eisenblätter, Michel; Faber, Cornelius & Wildgruber, Moritz
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Profiling specific cell populations within the inflammatory tumor microenvironment by oscillating-gradient diffusion-weighted MRI. Journal for ImmunoTherapy of Cancer, 11(3), e006092.
Hoffmann, Emily; Gerwing, Mirjam; Niland, Stephan; Niehoff, Rolf; Masthoff, Max; Geyer, Christiane; Wachsmuth, Lydia; Wilken, Enrica; Höltke, Carsten; Heindel, Walter L.; Hoerr, Verena; Schinner, Regina; Berger, Philipp; Vogl, Thomas; Eble, Johannes A.; Maus, Bastian; Helfen, Anne; Wildgruber, Moritz & Faber, Cornelius
