Hedgehog inhibitor sonidegib potentiates 177 Lu-octreotate therapy of GOT1 human small intestine neuroendocrine tumors in nude mice

Abstract

Background

¹⁷⁷Lu-octreotate can be used to treat somatostatin receptor expressing neuroendocrine tumors. It is highly effective in animal models, but clinical studies have so far only demonstrated low cure rates. Hedgehog inhibitors have shown therapeutic effect as monotherapy in neuroendocrine tumor model systems and might be one option to enhance the efficacy of ¹⁷⁷Lu-octreotate therapy. The aim of this study was to determine the therapeutic effect of combination therapy using ¹⁷⁷Lu-octreotate and the Hedgehog signaling pathway inhibitor sonidegib.

Methods

GOT1-bearing BALB/c nude mice were treated with either sonidegib (80 mg/kg twice a week via oral gavage), a single injection of 30 MBq ¹⁷⁷Lu-octreotate i.v., or a combination of both. Untreated animals served as controls. Tumor size was measured twice-weekly using calipers. The animals were killed 41 d after injection followed by excision of the tumors. Total RNA was extracted from each tumor sample and then subjected to gene expression analysis. Gene expression patterns were compared with those of untreated controls using Nexus Expression 3.0, IPA and Gene Ontology terms. Western blot was carried out on total protein extracted from the tumor samples to analyze activation-states of the Hh and PI3K/AKT/mTOR pathways.

Results

Sonidegib monotherapy resulted in inhibition of tumor growth, while a significant reduction in mean tumor volume was observed after ¹⁷⁷Lu-octreotate monotherapy and combination therapy. Time to progression was prolonged in the combination therapy group compared with ¹⁷⁷Lu-octreotate monotherapy. Gene expression analysis revealed a more pronounced response following combination therapy compared with both monotherapies, regarding the number of regulated genes and biological processes. Several cancer-related signaling pathways (i.e. Wnt/β-catenin, PI3K/AKT/mTOR, G-protein coupled receptor, and Notch) were affected by the combination therapy, but not by either monotherapy. Protein expression analysis revealed an activation of the Hh- and PI3K/AKT/mTOR pathways in tumors exposed to ¹⁷⁷Lu-octreotate monotherapy and combination therapy.

Conclusions

A comparative analysis of the different treatment groups showed that combination therapy using sonidegib and ¹⁷⁷Lu-octreotate could be beneficial to patients with neuroendocrine tumors. Gene expression analysis revealed a functional interaction between sonidegib and ¹⁷⁷Lu-octreotate, i.e. several cancer-related signaling pathways were modulated that were not affected by either monotherapy. Protein expression analysis indicated a possible PI3K/AKT/mTOR-dependent activation of the Hh pathway, independent of SMO.

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