Priming increases the anti-tumor effect and therapeutic window of 177Lu-octreotate in nude mice bearing human small intestine neuroendocrine tumor GOT1

Abstract

Background 177Lu-[DOTA0, Tyr3]-octreotate (177Lu-octreotate) is used for treatment of patients with somatostatin receptor (SSTR) expressing neuroendocrine tumors. However, complete tumor remission is rarely seen, and optimization of treatment protocols is needed. In vitro studies have shown that irradiation can up-regulate the expression of SSTR1, 2 and 5, and increase 177Lu-octreotate uptake.The aim of the present study was to examine the anti-tumor effect of a 177Lu-octreotate priming dose followed 24 h later by a second injection of 177Lu-octreotate compared to a single administration of 177Lu-octreotate, performed on the human small intestine neuroendocrine tumor cell line, GOT1, transplanted to nude mice.ResultsPriming resulted in a 1.9 times higher mean absorbed dose to the tumor tissue per administered activity, together with a reduced mean absorbed dose for kidneys. Priming gave the best overall anti-tumor effects. Magnetic resonance imaging showed no statistically significant difference in tumor response between treatment with and without priming. Gene expression analysis demonstrated effects on cell cycle regulation. Biological processes associated with apoptotic cell death were highly affected in the biodistribution and dosimetry study, via differential regulation of, e.g., APOE, BAX, CDKN1A, and GADD45A.ConclusionsPriming had the best overall anti-tumor effects and also resulted in an increased therapeutic window. Results indicate that potential biomarkers for tumor regrowth may be found in the p53 or JNK signaling pathways. Priming administration is an interesting optimization strategy for 177Lu-octreotate therapy of neuroendocrine tumors, and further studies should be performed to determine the mechanisms responsible for the reported effects.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-016-0247-y) contains supplementary material, which is available to authorized users.

The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines

“…GOT1 cells were derived from a liver metastasis and expressed neuroendocrine markers, including somatostatin receptor type 2 (SSTR2). This cell line has been used as a model for optimisation of SSTR2-mediated peptide receptor radionuclide therapy (PRRT) (Kölby et al 2005, Bernhardt et al 2007, Forssell-Aronsson et al 2013, Dalmo et al 2017. More recently, in 2009, three cell lines were established from a patient with metastatic SINET disease (Pfragner et al 2009).…”

Multiparametric MR for non‐invasive evaluation of tumour tissue histological characteristics after radionuclide therapy

“…The perfusion fraction ( f ) showed a significant correlation with the fractional tissue area of fibrosis (FD). Tissue response to irradiation may result in fibrotic tissue formation, and the GOT1 tumour model has demonstrated fibrosis in response to 177 Lu‐ocreotate therapy, as seen on MT staining . Few studies have correlated f with fibrosis in tumours.…”

“…Tissue response to irradiation may result in fibrotic tissue formation, and the GOT1 tumour model has demonstrated fibrosis in response to 177 Lu-ocreotate therapy, as seen on MT staining. 16,37 Few studies have correlated f with fibrosis in tumours. Residual lesions demonstrated significantly higher f in postchemoradiotherapy fibrosis compared with untreated tumours in nasopharyngeal carcinoma patients, 38 which is consistent with our results, but opposite correlations have been demonstrated in liver fibrosis.…”

“…As tumours reached 10–20 mm in diameter, 15 MBq 177 Lu‐octreotate (specific activity: 26 MBq/μg octreotate, IDB Holland, Baarle‐Nassau, the Netherlands) was injected intravenously, resulting in an absorbed dose to the tumour of approximately 4 Gy (cf. Dalmo et al ., 2017). The initial 21 animals were included in our mpMR project, including studies on the longitudinal behaviour of MR‐derived tissue parameters in response to therapy and optimization of image post processing techniques, both with different specific aims and results.…”

Identification of Potential MR-Derived Biomarkers for Tumor Tissue Response to 177Lu-Octreotate Therapy in an Animal Model of Small Intestine Neuroendocrine Tumor

“…MRI examinations were performed on day −1, 1, 3, 8, and 13. On day 0, 15 MBq 177 Lu-octreotate was administered intravenously in a tail vein, resulting in an extrapolated absorbed tumor dose of up to 4.0 Gy calculated according to the MIRD formalism [22] . The amount of 177 Lu-octreotate was chosen to give only partial remission to enable further analyses.…”