☆ 4.5 Article

Intratumoral heterogeneity after targeted therapy in murine cancer models with differing degrees of malignancy

TRANSLATIONAL ONCOLOGY (2023)

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TRANSLATIONAL ONCOLOGY

卷 37, 期 -, 页码 -

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ELSEVIER SCIENCE INC

DOI: 10.1016/j.tranon.2023.101773

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Therapy response assessment; Multiparametric MRI; Murine breast cancer; Tumor heterogeneity

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Oncology

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This study used non-invasive magnetic resonance imaging (MRI) to evaluate changes in tumor composition after targeted therapy in murine models of breast cancer. The results showed that different targeted treatments led to different intratumoral changes, and mp MRI can serve as a biomarker for treatment response assessment.

Introduction: Conventional morphologic and volumetric assessment of treatment response is not suitable for adequately assessing responses to targeted cancer therapy. The aim of this study was to evaluate changes in tumor composition after targeted therapy in murine models of breast cancer with differing degrees of malignancy via non-invasive magnetic resonance imaging (MRI). Materials and methods: Mice bearing highly malignant 4T1 tumors or low malignant 67NR tumors were treated with either a combination of two immune checkpoint inhibitors (ICI, anti-PD1 and anti-CTLA-4) or the multi tyrosine kinase inhibitor sorafenib, following experiments with macrophage-depleting clodronate-loaded liposomes and vessel-stabilizing angiopoietin-1. Mice were imaged on a 9.4 T small animal MRI system with a multiparametric (mp) protocol, comprising T1 and T2 mapping and diffusion-weighted imaging. Tumors were analyzed ex vivo with histology. Results and discussions: All treatments led to an increase in non-viable areas, but therapy-induced intratumoral changes differed between the two tumor models and the different targeted treatments. While ICI treatment led to intratumoral hemorrhage, sorafenib treatment mainly induced intratumoral necrosis. Treated 4T1 tumors showed increasing and extensive areas of necrosis, in comparison to 67NR tumors with only small, but also increasing, necrotic areas. After either of the applied treatments, intratumoral heterogeneity, was increased in both tumor models, and confirmed ex vivo by histology. Apparent diffusion coefficient with subsequent histogram analysis proved to be the most sensitive MRI sequence. In conclusion, mp MRI enables to assess dedicated therapy-related intratumoral changes and may serve as a biomarker for treatment response assessment.

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Multiparametric MRI enables for differentiation of different degrees of malignancy in two murine models of breast cancer

Mirjam Gerwing, Emily Hoffmann, Katharina Kronenberg, Uwe Hansen, Max Masthoff, Anne Helfen, Christiane Geyer, Lydia Wachsmuth, Carsten Hoeltke, Bastian Maus, Verena Hoerr, Tobias Kraehling, Lena Hiddessen, Walter Heindel, Uwe Karst, Melanie A. Kimm, Regina Schinner, Michel Eisenblaetter, Cornelius Faber, Moritz Wildgruber

Summary: Multiparametric MRI can non-invasively differentiate the degree of malignancy in breast cancer models by assessing tumor features such as structural composition and endothelial permeability.

FRONTIERS IN ONCOLOGY (2022)