Diffusion MRI and novel texture analysis in osteosarcoma xenotransplants predicts response to anti-checkpoint therapy

• Published in: PloS one Vol. 8; no. 12; p. e82875
• Main Authors: Foroutan, Parastou, Kreahling, Jenny M, Morse, David L, Grove, Olya, Lloyd, Mark C, Reed, Damon, Raghavan, Meera, Altiok, Soner, Martinez, Gary V, Gillies, Robert J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.12.2013; Public Library of Science (PLoS)
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Biocompatibility; Bioindicators; Biomarkers; Bone cancer; Bone Neoplasms - diagnosis; Bone Neoplasms - drug therapy; Bone Neoplasms - pathology; Cancer therapies; Cancer treatment; Cell cycle; Cell Cycle Checkpoints - drug effects; Chemotherapy; Cytotoxicity; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Diffusion Magnetic Resonance Imaging; Drugs; Entropy; Female; Gene expression; Health aspects; Humans; Immunohistochemistry; Magnetic resonance; Magnetic resonance imaging; Metabolism; Mice; Mice, SCID; Microscopy; Middle Aged; Molecular Targeted Therapy; NMR; Nuclear magnetic resonance; Osteosarcoma; Osteosarcoma - diagnosis; Osteosarcoma - drug therapy; Osteosarcoma - pathology; Prognosis; Pyrazoles - administration & dosage; Pyrimidines - administration & dosage; Sarcoma; Skewness; Studies; Therapy; Transplantation; Treatment Outcome; Tumors; Xenograft Model Antitumor Assays; Xenografts; Florida; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0082875

Combinations of targeted drugs have been employed to treat sarcomas, however, response rates have not improved notably, therefore emphasizing the need for novel treatments. In addition, imaging approaches to assess therapeutic response is lacking, as currently measurable indices, such as volume and/or diameter, do not accurately correlate with changes in tumor biology. In this study, quantitative and profound analyses of magnetic resonance imaging (MRI) were developed to evaluate these as imaging biomarkers for MK1775 and Gem in an osteosarcoma xenotransplant model at early time-points following treatment. Notably, we showed that Gem and Gem+MK1775 groups had significantly inhibited tumor growth by day 4, which was presaged by elevations in mean ADC by 24 hours post treatment. Significant differences were also observed at later time points for the Gem+MK1775 combination and MK1775 therapy. ADC distribution and entropy (randomness of ADC values) were also elevated by 24 hours following therapy. Immunohistochemistry demonstrated that these treatment-related increases in ADC correlated with apoptosis and observed cell condensations (dense- and exploded bodies). These findings underline the role of ADC as a quantitative imaging biomarker for therapy-induced response and show promising clinical relevance in the sarcoma patient population.