Biomarker discovery and assessment for prediction of kidney response after 177Lu-octreotate therapy

Abstract

Patients suffering from neuroendocrine tumors are oftentimes presented with spread disease at the time of diagnosis. Therapy using somatostatin analogs is today the only potentially curative treatment option for these patients. However, the kidneys are the dose-limiting organs in this type of therapy and the biological impact from radiopharmaceutical treatment is not fully understood. Furthermore, considering the large inter-individual variations in renal absorbed dose and toxicity, biomarkers for radiation damage would be of great significance in this type of therapy. The aims of this project were to study the normal kidney tissue response in vivo in mice following 177Lu and 177Lu-octreotate administration, to identify potential biomarkers following 177Lu exposure and evaluate their dependencies of absorbed dose, dose-rate, and time after injection, and to correlate these results with functional and morphological effects. The injected activity ranged between 0.3 and 150 MBq following 177Lu/177Lu-octreotate administration and the biological effect was investigated between 15 minutes and one year after administration. Transcriptional and miRNA variations were studied using microarray analysis and protein expression was investigated using mass spectrometry. Correlations between the transcriptional and protein variations were performed with functional parameters, as determined by 99mTc-DTPA/99mTc-DMSA scintigraphy, and with the morphological effects following 177Lu-octreotate administration. The number of differentially regulated transcripts following 177Lu/177Lu-octreoate administration was dependent on absorbed dose, dose-rate, time after injection, and tissue (kidney cortex or medulla) investigated. No transcript was found to be differentially regulated at all exposure conditions. The most recurrently regulated genes were the Serpina10 gene in kidney cortex, and the Egr1, Pck1, and Hmgcs2 genes in kidney medulla. Substantial differences in response were found between 177Lu-octreotate and 177LuCl3. Concerning the miRNA and protein data, a high absorbed dose-specificity was found, with few miRNAs/proteins found recurrently regulated at most exposure conditions. The transcriptional analyses showed a strong and diverse transcriptional response and the functional analyses revealed clear negative effects on renal function, with enhanced negative effects with absorbed dose and time after administration. Several potentially useful biomarkers were detected at the transcriptional level, markers with potential applicability in early prediction of late renal injury after 177Lu/177Lu-octreotate exposure.