Abstract 361: NT1195, a novel biguanide, exhibits superior uterine penetration and anti-tumorigenic efficacy as compared to metformin/phenformin in endometrial cancer

Objectives: Obesity and diabetes are associated with increased risk and worse outcomes in endometrial cancer (EC). Anti-diabetic biguanide drugs such as metformin/phenformin may have anti-tumorigenic effects by behaving as AMPK activators. Metformin requires organic cation transporters (OCTs) for entry into cells whereas phenformin is not as reliant on OCTs for cell entry. NT1195 (NovaTarg) is a novel biguanide designed to have greater affinity for the OCT1/3, PMAT and MATE1 transporters. Thus, we compared head-to-head the pharmacokinetic properties and anti-tumorigenic potential of metformin vs phenformin vs NT1195 in a genetically engineered mouse model of endometrioid EC (LKB1 fl/fl p53 fl/fl ). Methods: Pharmacokinetic parameters, including half-life, AUC, bioavailability and uterine concentration were measured in female control mice after oral dosing of metformin, phenformin and NT1195 (5 mg/kg oral for all drugs). AdCre was injected at 6 wks of age to induce invasive EC in LKB1 fl/fl p53 fl/fl mice. Following tumor onset, mice were treated with placebo vs metformin vs phenformin vs NT1195 for 4 wks (50 mg/kg, oral for all drugs). Results: NT1195 (> 24 hrs) had a longer half-life when compared to metformin (3.7 hrs) and phenformin (7.2 hrs). Drug bioavailability was heightened in the NT1195-treated mice when compared to metformin and phenformin (149 vs 83.5 vs 8.31%, respectively). The AUC (h*kg*ng/ml/mg) for NT1195 was significantly higher at 1143 than that of metformin (26) and phenformin (184). Drug accumulation in uterine tissue at 24 hrs post dose demonstrated markedly increased presence of NT1195 (45.4 ng/g), compared to metformin and phenformin, which yielded levels below the limits of quantification. NT1195 had increased anti-tumorigenic efficacy in LKB1 fl/fl p53 fl/fl mice, inhibiting tumor growth by 88% compared to 78% for metformin and 80% for phenformin (p Conclusions: When compared to metformin/phenformin, NT1196 had superior bioavailability, a longer half-life and greater uterine tissue penetration, culminating in improved efficacy in an EC mouse model. Thus, NT1195 may be a promising novel biguanide therapy in EC, particularly in women who want to avoid hysterectomy and preserve fertility or are poor surgical candidates. Citation Format: Katherine Tucker, Allison Staley, Yali Fan, Xiaoling Zhao, Yajie Yin, Ziwei Fang, Wenchuan Sun, Kenneth Batchelor, Nick Livingston, Chunziao Zhou, Victoria Bae-Jump. NT1195, a novel biguanide, exhibits superior uterine penetration and anti-tumorigenic efficacy as compared to metformin/phenformin in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 361.