Abstract 1666: Biomarkers for early detection of radiation nephropathy

Abstract

Abstract Purpose/Background: Chronic kidney disease is among the common late effects detected in patients receiving chemotherapy and/or radiotherapy. Currently, there are no biomarkers that allow detection of normal tissue toxicity in late responding organs such as kidney. Developing predictive biomarkers could help identify individuals that are at high risk for close follow-up and prophylactic treatments. Our studies show that miRNAs detectable in cell-free body fluids can be developed as biomarkers of acute radiation syndromes. In the present study, we sought to investigate the potential of serum and urine miRNAs as indicators of radiation induced kidney damage in rodent models. Methods and Results: An amplification-free hybridization based nCounter assay was optimized for evaluating the changes of miRNAs in body fluids. Comparison of cell-free miRNAs in urine as well as serum, collected from control versus irradiated mice, enabled us to identify candidate biomarkers that are potential indicators of radiation response. Over 40 miRNAs were detectable in urine samples collected from mice and over 80 miRNAs were detectable in serum. Molecules such as miR-1224, miR-804, miR-714 and miR-709 showed significant increase in their urine level after radiation, which peaked 6-8 hours after exposure to acute doses. On the other hand, markers such as miR-378 that are also abundant in urine did not show significant change after radiation, hence serving as an internal control. Comparison of urinary response in mice exposed to 2, 4, 6 and 8 Gy TBI revealed good dose response. Furthermore, the same markers exhibited a dose and time dependent changes following exposure to fractionated myeloablative regimen (6 × 2 Gy, bid) that is commonly used in leukaemia patients, prior to stem cell transplantation. Specifically, two of these biomarkers, miR-714 and miR-1224 exhibited a dose dependent increase in their serum level after fractionated or acute single dose exposure. In-situ hybridization displayed an overall increase in signals of miR-1224 and miR-714 at outer medulla after radiation. Increased signals detected in tubular epithelial cells indicate the possible tubular origin of the urinary miRNAs that are responsive to radiation. Conclusion: We have developed a panel of miRNAs for non-/minimally invasive detection of radiation response in kidney. Several of the urinary miRNA biomarkers exhibited a dose and time dependent changes, suggesting their potential as biomarkers for non-invasive evaluation of radiation response in organs such as kidney for which early detection of damage is a major challenge. Citation Format: Feifei Song, Jidhin Jacob, Arnab Chakravarti, Naduparambil K. Jacob. Biomarkers for early detection of radiation nephropathy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1666.