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Background <p>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 <sup>18</sup>F-FDG to explore tumour metabolism. <sup>18</sup>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 (<sup>99m</sup>Tc-NTP 15 − 5) and GAG CEST MRI. Immunohistochemistry, biochemical assays and RNA sequencing were performed to confirm in vivo observations.</p> Results <p>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 <sup>18</sup>F-FDG PET and GLUT-1 staining for the energetic one, CEST-MRI and pimonidazole for the hypoxic status and <sup>99m</sup>Tc-NTP 15 − 5 SPECT and sGAG assay for proteoglycans. Genomic analysis shown changes in gene expression related to therapy.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月27日

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  • Roxane Autissier,
  • Guilhem Pagés,
  • Erwan Boutault,
  • Jean-Marie Bonny,
  • Sébastien Schmitt,
  • Philippe Auzeloux,
  • Yannick Bidet,
  • Flora Ponelle-Chachuat,
  • Aurélie Dutour,
  • Elisabeth Miot-Noirault,
  • Leslie Mazuel

摘要

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 18F-FDG to explore tumour metabolism. 18F-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 (99mTc-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 18F-FDG PET and GLUT-1 staining for the energetic one, CEST-MRI and pimonidazole for the hypoxic status and 99mTc-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.