Evaluation of preclinical efficacy of everolimus and pasireotide in thyroid cancer cell lines and xenograft models

Abstract

Background Signaling through mTOR and somatostatin pathway is implicated in thyroid cancer development. Method We evaluated everolimus, an mTOR inhibitor and pasireotide, a multi receptor somatostatin analogue as potential therapy of thyroid cancer focusing on the in vitro and in vivo efficacy, as well as possible mechanism to explain any observed interaction. Results Both everolimus and pasireotide inhibit the growth of thyroid cancer cell lines in vitro with varied efficacy that correlates with tumor origin and somatostatin receptor (SSTR) expression profile of the cell lines. In vitro activity of everolimus show positive correlation with the expression of SSTR types 1, 4 and 5 (CC: 0.9; 0.85, 0.87) while pasireotide activity show negative correlation with SSTR2 (CC: -0.87). Although there is greater modulation of pS6 when pasireotide is combined with everolimus, there is no significant abrogation of the expected feedback upregulation of AKT induced by everolimus. Also, the combination is not significantly better than each agent alone in short and long term in vitro assays. Continuous administration of everolimus at a low dose as opposed to high intermittent dosing schedule has greater antitumor efficacy against thyroid cancer xenografts in vivo . Pasireotide LAR has modest in vivo efficacy and the combination of everolimus and pasireotide LAR achieve greater tumor growth inhibition than each agent alone in TPC-1 xenograft model of thyroid cancer (p = 0.048). Conclusion Our findings provide support for the clinical evaluation of everolimus and pasireotide in thyroid cancer and other neuroendocrine tumors.

Molecular Alterations in Thyroid Cancer: From Bench to Clinical Practice

“…Since activation of the somatostatin receptor (SSTR1-5) also inhibits PI3K/AKT signaling, the somatostatin analog pasireotide has been tested in combination with everolimus [154]. Pasireotide activates SSTRs, in particular, subtype 2, which is the most expressed somatostatin receptor in thyroid cancers [155].…”

A Multicenter Randomized Phase II Study of Single Agent Efficacy and Optimal Combination Sequence of Everolimus and Pasireotide LAR in Advanced Thyroid Cancer

“…For instance, aberrant signaling in the PI3K/AKT/mTOR pathways is directly implicated as contributing to the development of MTC and DTC [ 22 , 24 , 25 , 26 ]. Additionally, based on the high expression of somatostatin receptor in thyroid cancer, somatostatin analogues are expected to have clinical benefit in thyroid cancer [ 18 ]. Indeed, octreotide and lanreotide, which have strong affinity for somatostatin receptor subtype 2, were previously explored for the treatment of advanced thyroid cancer and showed modest clinical activity in the form of biochemical response and symptomatic relief [ 5 , 6 , 7 , 8 , 27 , 28 ].…”

“…Conversely, a dual blockade of the mTOR and alternative survival pathways results in increased efficacy [ 12 , 13 , 14 ]. The combination of somatostatin analogue octreotide and mTOR inhibitor everolimus led to greater efficacy in preclinical models of thyroid cancer and clinically in pancreatic neuroendocrine tumors [ 16 , 17 , 18 ]. Because somatostatin analogue sensitizes tumor cells to mTOR inhibition and can also reverse resistance to mTOR inhibition through its inhibition of Akt [ 19 , 20 ], we expect that the combination of pasireotide long-acting release (LAR) and everolimus will result in even greater antitumor efficacy.…”

Recent advances in the management of anaplastic thyroid cancer

“…Constitutive activation of the phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR pathway has been reported in thyroid cancer pathogenesis. Everolimus is a Sirolimus-derived mTOR inhibitor, whose activity against several thyroid cancer cell lines has been confirmed both in vitro and in vivo [ 91 ]. In experimental studies, Everolimus provided growth inhibition in ATC cell lines harboring a PI3K mutation, which made those cells Gefitinib-resistant, thus suggesting a possible correlation between its efficacy and PI3K/Akt/mTOR signaling pathway alteration [ 92 ].…”