Abstract 4657: Targeting STAT3 for mammary cancer prevention in MMTV/Neu mice employing the antagonist GLG-302

Abstract

Abstract GLG-302 (S3I-201, NSC 74859) from the National Cancer nstitute chemical libraries was identified as a STAT3 antagonist using structure-based virtual screening with a computer model of the Stat3 SH2 domain bound to its Stat3 phosphotyrosine peptide derived from the x-ray crystal structure of the Stat3 homodimer. In addition to preclinical therapeutic efficacy in breast, glioma, and pancreatic cancer, it ameliorated the resistance to cetuximab and doxorubicin in models of liver cancer. It was well tolerated in mice, rats and dogs in pilot safety studies. Since our laboratories have shown that activated STAT3 is present in normal mammary tissue of young mice and mammary cancers, we evaluated the efficacy of GLG-302, given orally, for its preventive activity in female MMTV-Neu mice that develop spontaneous estrogen receptor negative (ER−) mammary cancers. Previous studies had shown that acute dosing with GLG-302 would suppress the growth of established mammary cancers in mouse models at tolerable doses. We conducted a dose selection study lasting 3 months indicating that doses of GLG-302 as high as 500 mg/kg BW/day (administered by gavage 5X/week) would not alter body weights or induce other signs of toxicity. Proliferation rates (Ki67) in the mammary glands of the mice, determined after 2 weeks and after 3 months of GLG-302 administration, revealed that this dose of the agent caused reductions of 66% and 55%, respectively. A cancer prevention efficacy study was then initiated that included the following groups (15 mice/group); Group 1, GLG-302 (500 mg/kg BW/day); Group 2, GLG-302 (250 mg/kg BW/day); Group 3, GLG-302 (125 mg/kg BW/day); Group 4, Lapatinib (100 mg/kg BW/day) as a positive control; and Group 5, no treatment. Treatment (5X/week) was initiated when the mice were 65 days of age, and will continue for 10 months. Mammary tumors are detected by palpation of the mice 2X/week. The study is currently 5 months after the initial GLG-302 treatment. Average palpable mammary tumor number in each group is: Group 1, 0.07; Group 2, 0.33, Group 3, 0.50, Group 4, 0.08, and Group 5, 1.20. The 94% reduction in the average number of mammary tumors observed in mice receiving the high dose of GLG-302 compared to that in the no treatment group; and is comparable to the reduction observed following treatment with lapatinib. No body weight loss or other toxicity has been observed. In conclusion, IHC data demonstrated that GLG-302 can target the normal mammary epithelial cells of the mouse mammary gland during well-tolerated chronic dosing of the agent. Furthermore, current data in the prevention study has demonstrated a dose-dependent decrease in spontaneous mammary tumors in female MMTV/Neu mice. Additional studies using GLG-302 are ongoing in the dimethylbenzanthracene-induced mammary cancer (ER+) rat model, and will be presented. Studies supported by NCI contract HHSN261201200021I. Citation Format: Robert H. Shoemaker, Michael W. Lovell, John J. Whalen, Fariba Moeinpour, Clinton J. Grubbs. Targeting STAT3 for mammary cancer prevention in MMTV/Neu mice employing the antagonist GLG-302. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4657. doi:10.1158/1538-7445.AM2015-4657