NAMPT Inhibitor GMX1778 Enhances the Efficacy of 177Lu-DOTATATE Treatment of Neuroendocrine Tumors.
Neuroendocrine tumors (NETs) can be treated by peptide receptor radionuclide therapy using radiolabeled somatostatin analogs. However, the efficacy of such treatment is low and needs to be optimized. Our study evaluated the potential radiosensitizing effects of inhibition of nicotineamide phosphoribosyltransferase on177Lu-DOTATATE treatment in a NET model.



Nude mice xenografted with the human NET cell line GOT1 were treated with semiefficient doses of177Lu-DOTATATE (7.5 MBq, intravenously) or the nicotineamide phosphoribosyltransferase inhibitor GMX1778 (100 mg/kg/wk, orally).



Median time to tumor progression (tumor volume larger than at day 0) was 3 d for controls, 7 d for single-dose GMX1778, 28 d for single-dose177Lu-DOTATATE, 35 d for 3 weekly doses of GMX1778, and 98 d for combined treatment with177Lu-DOTATATE and GMX1778 × 1. After177Lu-DOTATATE and 3 weekly doses of GMX1778, none of the tumors progressed within 120 d.



GMX1778 enhances the efficacy of177Lu-DOTATATE treatment and induces a prolonged antitumor response.
Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden anna-karin.elf@vgregion.se.
Anna-Karin
AK
Elf
Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; and.
Peter
P
Bernhardt
Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Sweden.
Tobias
T
Hofving
Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Sweden.
Yvonne
Y
Arvidsson
Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; and.
Eva
E
Forssell-Aronsson
Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
Bo
B
Wängberg
Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Sweden.
Ola
O
Nilsson
Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
Viktor
V
Johanson
D000818:Animals; D003486:Cyanides / Q000008:administration & dosage*; D016207:Cytokines / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006146:Guanidines / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018358:Neuroendocrine Tumors / Q000473:pathology* / Q000628:therapy*; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors*; D015282:Octreotide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D009942:Organometallic Compounds / Q000008:administration & dosage*; D011836:Radiation Tolerance / Q000187:drug effects*; D019275:Radiopharmaceuticals / Q000008:administration & dosage; D016896:Treatment Outcome
D003486:Cyanides; D016207:Cytokines; D006146:Guanidines; C401312:N-(6-chlorophenoxyhexyl)-N''-cyano-N''-4-pyridylguanidine; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; C447941:lutetium Lu 177 dotatate; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; D015282:Octreotide
177Lu-DOTATATE; GMX1778; NAMPT inhibitor; neuroendocrine tumor (NET); peptide receptor radionuclide therapy