Abstract 605: Intermittent treatment of hormone-dependent breast cancer using exemestane: Translational research from lab bench to bedside

Abstract

Abstract Although aromatase inhibitors (AIs) are useful in the treatment of hormone-responsive breast cancer, unfortunately, resistance to such therapy still develops. Based on our published preclinical results that ER, AREG and EGFR play important roles in the acquired resistance mechanism of exemestane (EXE), a steroidal AI, intermittent use of EXE was thought to delay the development of acquired resistance by preventing up-regulation of AREG and activation of EGFR-mediated pathways. This hypothesis was verified by preclinical cell culture and animal studies. Microarray analysis was performed using RNA isolated from week-14 (EXE-resistant) MCF7aro cells that were continuously treated with EXE, week-14 (EXE-responsive) cells that were intermittently treated with EXE (2 weeks on and 1 week off), and cells without EXE treatment. A selective number of estrogen-regulated genes, including AREG and SGK3 (serum/glucocorticoid regulated kinase family member 3), were differentially transcribed between the continuously treated samples and intermittently treated samples. Treatment of EXE resistant cells with siRNAs against AREG and SGK3 suppressed cell growth, supporting the roles of these two proteins in the development of resistance to EXE. Additional results from ChIP and gene expression analyses confirm that the expression of SGK3 can be up-regulated by E2 as well as EXE, and over-expression of SGK3 suppresses apoptosis and increases cell survival. Our animal experiments revealed that intermittent treatment of EXE (250 µg/day, 2 weeks on and 1 week off) was effective at suppressing androgen-induced MCF7aro tumor growth in nude mice, and that after 21 weeks of treatment, resistance resulted in continuous EXE treatment group, while the tumor volumes in the positive control group (androgen treated only) reached 10 cm3 at week 18. qPCR analysis indicated that SGK3 expression in tumors from continous EXE mice was two times that in tumors from the positive control mice, with lowest expression in tumors from the intermittent EXE group (30% of that of the positive control). An analysis on 11 pairs of malignant and adjacent normal tissue has revealed that SGK3 expression is significantly greater in breast tumor specimens than adjacent non-cancer specimens (P=0.006). Since results from these translational research studies provide an important mechanistic basis for intermittent EXE therapy, a clinical trial to evaluate the intermittent use of EXE on postmenopausal women with ER-positive metastatic breast cancer has been recently approved and initiated at the City of Hope NCI-designated Comprehensive Cancer Center. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 605.