Antitumor Effect of Everolimus in Preclinical Models of High-Grade Gastroenteropancreatic Neuroendocrine Carcinomas

Abstract

Background/Aims: While the range of therapeutic options for well-differentiated gastroenteropancreatic neuroendocrine tumors has recently increased with the emergence of targeted therapies, such as mTOR inhibitors, there is no recent progress in the treatment of poorly differentiated neuroendocrine carcinomas (PDNECs). Since PDNECs have been shown to strongly express mTOR pathway components, the aim of the present study was to assess the antitumor effect of the mTOR inhibitor everolimus in preclinical models of PDNECs. Methods: The expression of mTOR pathway components and their response to everolimus were assessed in two neuroendocrine cell lines: STC-1 and GluTag. A xenograft model of intrahepatic dissemination in the nude mouse, based on the intrasplenic injection of either STC-1 and GluTag tumor cells, was used. Animals were started on everolimus treatment 3 days after injection. The effects of treatment on tumor growth, proliferative capacities, apoptosis and in situ expression of mTOR pathway components were assessed. Results: The expression of mTOR pathway components was comparable in STC-1 and GluTag cells and in human PDNECs and could be inhibited in vitro by everolimus. In vivo, the tumor volume of STC-1 and GluTag xenografts was significantly reduced in treated animals (6.05 ± 1.84% as compared to 21.76 ± 3.88% in controls). Everolimus treatment also induced a significant decrease in Ki67 index and in the phosphorylation levels of the two major effectors of mTOR, p70S6K and 4E-BP1. Conclusion: Our experimental data suggest that mTOR inhibition could be considered a therapeutic option for high-grade gastroenteropancreatic neuroendocrine tumors.

Everolimus in the treatment of neuroendocrine tumors: efficacy, side-effects, resistance, and factors affecting its place in the treatment sequence

“…With respect to the PDNEC, several immunohistochemical analyses reveal high expression and activation of mTOR [7,133], and an anti-proliferative effect of everolimus was shown in a preclinical study[134]. A case study reported a patient with PDNEC who was successfully treated with everolimus for 15 months[135].…”

Unmet Needs in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms (WHO G3)

“…The mTOR pathway is upregulated in 70-80% of NEC and the mTOR inhibitor everolimus was shown to be effective in a preclinical GEP NEC model [55][56][57]. An ongoing German multicenter study (EVINEC) is using everolimus as a second-line treatment for NEN G3 (NCT02113800).Everolimus was given to 15 patients with pancreatic NET G3 with Ki-67 ≤55%, mainly after first-line treatment; the results were promising, with a median PFS of 6 months and an OS of 28 months after the start of everolimus treatment [58].…”

Combined therapy with RAD001 e BEZ235 overcomes resistance of PET immortalized cell lines to mTOR inhibition

“…For instance, low expression levels of negative regulators of mTOR, such as PTEN and the TSC1/2 complex, are associated with worse prognosis in PET patients [7]. Moreover, a number of studies have confirmed the efficacy of RAD001 in models of neuroendocrine tumours in vitro [11, 12]. However, despite the strong rationale and the specific mechanism of action of RAD001, not all patients respond to the treatment.…”