mTOR Inhibitor RAD001 Promotes Metastasis in a Rat Model of Pancreatic Neuroendocrine Cancer

Stefan Pool, Sander Bison, Stuart Koelewijn, Linda Graaf, Marleen Melis, Eric Krenning, Marion Jong

Research output: Contribution to journalArticleAcademicpeer-review

35 Citations (Scopus)

Abstract

Inhibition of mTOR is commonly considered a valid target in cancer treatment, but this assertion does not address effects on the immune microenvironment that may be detrimental to cancer treatment. Here we show how administration of the mTOR inhibitor RAD001 (everolimus) results in the occurrence of distant metastasis in a rat model of pancreatic cancer. RAD001 was administered twice weekly for 4.5 weeks as a single treatment or combined with [Lu-177-DOTA,Tyr3] octreotate (Lu-177-DOTATATE), where the latter targets the somatostatin receptor-2. The hypothesized synergistic therapeutic effect of RAD001 combined with Lu-177-DOTATATE was, however, not observed in our experiments. The combination was shown to be less effective than Lu-177-DOTATATE alone. Unexpectedly, tumor metastasis was observed in 77% of the subjects treated with RAD001, either alone or as part of the combination treatment. This was a striking effect, because metastasis did not occur in control or Lu-177-DOTATATE-treated animals, including those where the primary tumor was surgically removed. These findings may be important clinically among noncompliant patients or patients that discontinue RAD001 therapy because of adverse effects. Cancer Res; 73(1); 12-18. (C) 2012 AACR.
Original languageUndefined/Unknown
Pages (from-to)12-18
Number of pages7
JournalCancer Research
Volume73
Issue number1
DOIs
Publication statusPublished - 2013

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