Lutetium-177-octreotate treatment of small intestine neu-roendocrine tumors - Radiation biology as basis for optimization

Patients with neuroendocrine tumors (NETs) often have metastatic spread at the time of diagnosis. NETs frequently express somatostatin receptors (SSTR) that can be targeted by radiolabeled somatostatin analogs (e.g. 177Lu-octreotate). Despite being highly effective in animal models (e.g. the human small intestine NET GOT1 transplanted to nude mice), 177Lu-octreotate-based therapies have shown low cure rates in clinical studies. The cellular processes that underlie positive treatment response to 177Lu-octreotate are largely unknown. The aim of this work was to study the possibilities to optimize the therapeutic effects of 177Lu-octreotate in the GOT1 model in nude mice. A literature study of available data on radiolabeled somatostatin analogs on NETs in animal models was performed, to identify strategies for treatment optimization. To test these strategies, GOT1-bearing BALB/c nude mice were treated with non-curative amounts of 177Lu-octreotate in different treatment schedules including single administrations, priming (fractionated) administrations and combination treatment with hedgehog inhibitor sonidegib. Biodistribution and dosimetry studies were performed and anti-tumor effects were monitored by measuring tumor volume. Global transcriptional and proteomic responses in tumor samples were evaluated using RNA microarray and liquid chromatography mass spectrometry, respectively. 177Lu-octreotate therapy of GOT1 tumors xenotransplanted in nude mice resulted in tumor volume reduction. Priming administration resulted in increased anti-tumor effects and increased therapeutic window. Combination therapy using sonidegib and 177Lu-octreotate resulted in prolonged time to progression. The global transcriptional and proteomic analyses of 177Lu-octreotate treated tumor samples revealed time-specific responses in terms of affected biological functions. In conclusion, time-dependent changes in p53-related cell cycle regulation and apoptosis, angiogenesis, endoplasmic reticulum stress, and oxidative stress-related processes suggest possible niches for combination therapy at different time points after radionuclide therapy. Priming 177Lu-octreotate therapy and combination therapy using sonidegib and 177Lu-octreotate could be beneficial to patients with NE-tumors