Jerome Lacombe, PhD, Alain Mange, PhD, Alan Nordquist, Jerome Solassol, PhD, MD, David Azria, PhD, MD, Frederic Zenhausern, PhD; University of Arizona; University of Montpellier; Montpellier Cancer Institute
BACKGROUND: Biomarkers that predict late normal tissue reactivity to radiation therapy (RT) are necessary to personalize treatments, leading to clinical benefit optimization. The ex vivo 8-Gy radiation-induced lymphocyte apoptosis (RILA) assay is the most promising assay for clinical use. This assay showed an inverse correlation between the occurrence of radiation-induced late toxicity (RILT) and RILA values.
METHODS AND RESULTS: To improve the positive predictive value of this assay, we performed a quantitative proteomic approach and identified five proteins (AK2, ANXA1, APEX1, HSPA8, and IDH2) involved in redox homeostasis regulation. These proteins are significantly overexpressed in ex vivo 8 Gy–irradiated lymphocytes of patients presenting with RILT but not in patients without late toxicity after curative intent RT. Additional experiments showed a significant increase in radiation-induced radical oxygen species production and NADPH oxidase mRNA expression in patients with RILT.
DISCUSSION: These findings highlight the essential role of radiation-induced oxidative stress in establishing late radiotoxicity, especially irradiation-dependent activation of NADPH oxidase. This knowledge will pave the way for new proteins that are predictive of radiosensitivity. However, it is necessary to work out a protein assay that is fast and highly reproducible, quantitative, specific, and sensitive for use in clinical settings. Therefore, we are developing a new integrated microfluidic platform for automating the proteomic assay. From a small volume of fingerstick-based blood collection, using microfluidic technology, we design a one-step assay within a microfluidic cartridge that integrates several modules for the preparation of a biological sample, running the protein assay measurements and performing the data analysis.
CONCLUSIONS: Such a platform technology will allow a point-of-care assay to be set up for the prediction of normal tissue toxicity after RT and ultimately for the monitoring of any intracellular protein assay diagnostic method.
Proceedings of the 98th Annual Meeting of the American Radium Society — americanradiumsociety.org