title: mTOR inhibitor RAD001 promotes metastasis in a rat model of pancreatic neuroendocrine cancer.
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 [(177)Lu-DOTA,Tyr3]octreotate ((177)Lu-DOTATATE), where the latter targets the somatostatin receptor-2. The hypothesized synergistic therapeutic effect of RAD001 combined with (177)Lu-DOTATATE was, however, not observed in our experiments. The combination was shown to be less effective than (177)Lu-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 (177)Lu-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.
authors.affiliation: Department of Nuclear Medicine and Radiology, Erasmus MC, Rotterdam, The Netherlands. s.pool@erasmusmc.nl
authors.forename: Stefan E
authors.initials: SE
authors.lastname: Pool
authors.forename: Sander
authors.initials: S
authors.lastname: Bison
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Koelewijn
authors.forename: Linda M
authors.initials: LM
authors.lastname: van der Graaf
authors.forename: Marleen
authors.initials: M
authors.lastname: Melis
authors.forename: Eric P
authors.initials: EP
authors.lastname: Krenning
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D000068338:Everolimus; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D051381:Rats; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus