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

• Type of Material: Article
• Authors: Taofeek Owonikoko, Emory University; Guojing Zhang, Emory University; Shenila B. Lallani, Emory University; Zhengjia Chen, Emory University; Deborah E. Martinson, Emory University; Fadlo R. Khuri, Emory University; Sagar Lonial, Emory University; Adam Marcus, Emory University; Shi-Yong Sun, Emory University
• Language: English
• Date: 2019-02-26
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2019 Owonikoko et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0206309
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 14
• Issue: 2
• Start Page: e0206309
• End Page: e0206309
• Grant/Funding Information: This work was supported in part by the National Cancer Institute at the National Institutes of Health Cancer Center Support Grant (NIH/NCI P30CA13829) in support of the Biostatistics and Bioinformatics Shared resource of Winship Cancer Institute of Emory University. Novartis Pharmaceuticals Corporation; CSOM230XUS25T (TKO).
• Keywords: MAMMALIAN TARGET; Multidisciplinary Sciences; RAPAMYCIN; RECEPTOR; EXPRESSION; PROLIFERATIVE SIGNALS; Science & Technology; SOMATOSTATIN ANALOGS; KINASE; IN-VIVO; INHIBITION; Science & Technology - Other Topics; SOM230
• Research Categories: Biology, Biostatistics; Health Sciences, Oncology

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.