Identification of Potential Biomarkers for Cancer Cachexia and Anti-Fn14 Therapy

SIMPLE SUMMARY: Cancer cachexia is an underestimated condition with huge impact on survival and quality of life for many cancer patients. Currently, there is no reliable diagnosis for this condition, particularly for cancer cachexia at an early stage. The aim of our study is to develop potential biomarkers that can be used not only for diagnosing cancer cachexia but also evaluating potential anti-cachexia therapy such as anti-Fn14 mAb treatment. We identified several circulating biomarkers for cancer cachexia and confirmed that LCN2 is a promising biomarker for cancer cachexia in humans. These biomarkers could accelerate both diagnosis and clinical trials for cancer cachexia. ABSTRACT: Background: Developing therapies for cancer cachexia has not been successful to date, in part due to the challenges of achieving robust quantitative measures as a readout of patient treatment. Hence, identifying biomarkers to assess the outcomes of treatments for cancer cachexia is of great interest and important for accelerating future clinical trials. Methods: We established a novel xenograft model for cancer cachexia with a cachectic human PC3* cell line, which was responsive to anti-Fn14 mAb treatment. Using RNA-seq and secretomic analysis, genes differentially expressed in cachectic and non-cachectic tumors were identified and validated by digital droplet PCR (ddPCR). Correlation analysis was performed to investigate their impact on survival in cancer patients. Results: A total of 46 genes were highly expressed in cachectic PC3* tumors, which were downregulated by anti-Fn14 mAb treatment. High expression of the top 10 candidates was correlated with low survival and high cachexia risk in different cancer types. Elevated levels of LCN2 were observed in serum samples from cachectic patients compared with non-cachectic cancer patients. Conclusion: The top 10 candidates identified in this study are candidates as potential biomarkers for cancer cachexia. The diagnostic value of LCN2 in detecting cancer cachexia is confirmed in patient samples.