NAMPT Inhibitor GMX1778 Enhances the Efficacy of¹⁷⁷Lu-DOTATATE Treatment of Neuroendocrine Tumors

Abstract

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 on 177 Lu-DOTATATE treatment in a NET model. Methods: Nude mice xenografted with the human NET cell line GOT1 were treated with semiefficient doses of 177 Lu-DOTATATE (7.5 MBq, intravenously) or the nicotineamide phosphoribosyltransferase inhibitor GMX1778 (100 mg/kg/wk, orally). Results: 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-dose 177 Lu-DOTATATE, 35 d for 3 weekly doses of GMX1778, and 98 d for combined treatment with 177 Lu-DOTATATE and GMX1778 · 1. After 177 Lu-DOTATATE and 3 weekly doses of GMX1778, none of the tumors progressed within 120 d. Conclusion: GMX1778 enhances the efficacy of 177 Lu-DOTATATE treatment and induces a prolonged antitumor response.

Combination of 5-Fluorouracil with Epigenetic Modifiers Induces Radiosensitization, Somatostatin Receptor 2 Expression, and Radioligand Binding in Neuroendocrine Tumor Cells In Vitro

“…To improve the therapeutic efficacy of PRRT in NETs, different strategies have been investigated as follows: several clinical studies using fluoropyrimidine-based chemotherapy regimens for PRCRT in NET patients (3,(5)(6)(7)(8), preclinical studies using epigenetic modifiers as DNMT inhibitors/HDAC inhibitors to upregulate SSTR expression (12,13) and radioligand binding (12,13), preclinical studies using novel molecular target compounds for PRCRT (17)(18)(19), and variation of radiopharmaceuticals by the use of the a-emitters 215 Act or 213 Bis (20) or by the use of somatostatin antagonists (21). In preclinical studies, Taelman et al (12) and Veenstra et al (13) reported that several DNMT inhibitors and HDAC inhibitors induce SSTR mRNA transcription and protein expression and enhance specific SSTR-mediated radioligand binding of NET cells.…”

Inhibitor of Nicotinamide Phosphoribosyltransferase Sensitizes Glioblastoma Cells to Temozolomide via Activating ROS/JNK Signaling Pathway

“…Recently, Tateishi et al reported that NAMPT inhibitor conferred metabolic susceptibility in IDH1 mutant gliomas [35]. The NAMPT inhibitor GMX1778 also enhanced the efficacy of radiolabeled somatostatin analog 177 Lu-DOTATATE treatment and induces a prolonged antitumor response [36]. …”

The next generation of peptide receptor radionuclide therapy

“…A similar approach successfully tested in vivo is the combination of PRRT with a nicotineamide phosphoribosyltransferase (NAMPT) inhibitor that blocks nicotinamide-adenine-dinucleotide (NAD + ) regeneration after consumption by PARP. The NAMPT inhibitor GMX1778 produced a synergistic antitumor effect on GOT1 xenografts in mice treated with PRRT (Elf et al 2017). Furthermore, a preclinical study showed that Hedgehog inhibitors can function as radiosensitisers of PRRT.…”