Summary

Cachexia is a complex syndrome characterized by unintentional weight loss, progressive muscle wasting and loss of appetite. Anti-Fn14 antibody (mAb 002) targets the TWEAK receptor (Fn14) in murine models of cancer cachexia and can extend the lifespan of mice by restoring the body weight of mice. Glucose metabolic changes were investigated in murine models of cachexia via [¹⁸F]FDG PET imaging, to explore whether Fn14 plays a role in the metabolic changes that occur during cancer cachexia.

Results from nanoScan^® PET/MRI

All animals were injected with 14.8 MBq [¹⁸F]FDG. 15 min static, whole-body acquisition was performed using a dedicated small animal nanoPET/MR camera (nanoScan®, Mediso, Budapest, Hungary). The multimodality image datasets were archived from the Mediso hybrid imaging systems to a PACS server via DICOM transfer. The co-registration of multi-modality scans, markup of volumes of interest (VOIs) and quantitative image analysis were performed using PMOD 3.8 (PMOD Technologies LLC, Zurich, Switzerland).

• Utilising whole body [¹⁸F]FDG PET imaging, an increase of glucose uptake over time was observed in tumours and brain of cachexia-inducing versus non-cachexia-inducing tumour-bearing mice, suggesting a higher glucose metabolic activity in tumours of cachectic mice.
• Tumour uptake calculated as percentage injected dose per cubic centimeter (%ID/cc) of tissue confirmed reduced [¹⁸F]FDG uptake in tumours of C26-tumour-bearing mice treated with mAb 002. Quantitative PET analysis of brain, lung and muscle tissue showed a small but not significant increase in brain uptake.

Figure 2 d Whole-body PET (maximum intensity projection), whole-body MR (surface rendered) and fused PET/MR images on day 14 of three per treatment group (PBS, left column; mAb 002, right column). Red arrows indicate location of the tumours.

Conclusions

The tumour microenvironment (TME) and the tumour are known to be metabolically distinct from normal tissues, and this environment may drive cancer-cachexia specific Fn14 pathways. Cancer cells have adapted via many alterations to promote survival, growth, migration, invasion, and metastasis, one of the most distinctive is the ability to metabolise glucose to lactate. This appears to be advantageous to cell growth despite less ATP is generated per molecule of glucose compared to oxidative phosphorylation. It has been proposed that the TME may directly contribute to tumour cell metabolism by limiting the availability of glucose and creating an environment of nutrient competition in surrounding cells and triggering a hypoxic state. Hypoxia corresponds with a decrease in ATP generation through oxidative phosphorylation and an increase in glycolysis. The results of the study summarized in this article suggest for the first time a role for Fn14 in altered glycolytic capacity of tumour cells. A clinical trial with [¹⁸F]FDG PET in cachectic patients is currently ongoing to further evaluate the authors’ observations.

Original link Springer Nature