Bimodality imaging as a companion to evaluate antitumour efficacy of TH-302 in experimental chondrosarcoma.

BACKGROUND: The hypoxic status of cancer tumour is disparate within tumour microenvironment and is considered as the main cause of treatment resistance. Chondrosarcoma, a type of bone cancer, combines heterogonous tumour microenvironment and resistance to therapies. We aimed to image tumour microenvironment response to hypoxia activated prodrug therapy with Evofosfamide (TH-302) on a rat chondrosarcoma model thanks to an original multimodal imaging strategy. Bimodal imaging strategy consisted of nuclear imaging and MRI on TH-302 treated and control animals. To monitor TH-302 effects on tumour growth and structure, we measured T2 and ADC by MRI and we used (18)F-FDG to explore tumour metabolism. (18)F-FMISO and APT to Guanidyl ratio CEST MRI evaluated hypoxic status. Proteoglycans in the extracellular matrix were explored in vivo by a radiotracer targeting proteoglycans ((99m)Tc-NTP 15 - 5) and GAG CEST MRI. Immunohistochemistry, biochemical assays and RNA sequencing were performed to confirm in vivo observations. RESULTS: TH-302 demonstrated a strong efficacy on tumour structure with a reduction of its volume of 75% at the end of the protocol, a modification of the tumour microstructures and a decreased of both cellularity and cell proliferation. The drug also modified the tumour metabolisms as shown by (18)F-FDG PET and GLUT-1 staining for the energetic one, CEST-MRI and pimonidazole for the hypoxic status and (99m)Tc-NTP 15 - 5 SPECT and sGAG assay for proteoglycans. Genomic analysis shown changes in gene expression related to therapy. CONCLUSIONS: TH-302 shows an in vivo anti-tumour activity in chondrosarcoma. Our multimodal imaging approach allows monitoring complex exchanges between tumour cells and their neighboring under therapy.