Combination of HDACi entinostat (SNDX-275) with letrozole provides control over tumor growth in MDA-MB-231 xenograft model.

Abstract

Abstract Abstract #6128 It is well established that approximately 75% of human breast cancers are ER+ and therefore treated with endocrine therapy. In a past few decades endocrine therapy has made significant advancements. However, the application of these agents is limited to ER+ cancers since ER- patients are unresponsive to endocrine therapy primarily due to lack of ER expression in the tumor. The main purpose of this project is to determine whether ER- breast cancer tumors that display poor anti-proliferative response to aromatase inhibitor (AI) letrozole, can be sensitized by co-treatment with HDACi entinostat. Based on preliminary studies, we hypothesize that by inhibiting HDAC ER is re-expressed making the cells sensitive to the anti-proliferative effects of AIs. In our previous studies we have shown that HDACi entinostat can revert the ERα repression and upregulate ERα and aromatase in vitro and in vivo. In this study we are showing that this activation of aromatase and re-expression of ERα renders ER- breast cancer tumors (xenografts of MDA-MB-231 cells) responsive to letrozole.
 MDA-MB-231 xenografts were grown in ovariectomized female nude mice. Mice were inoculated with 2.5X 106 cells per site subcutaneously. When the tumors reached a measurable size ∼150 mm3, the mice were grouped into 6 groups (n=10), such that the mean tumor volumes across the groups was not statistically different (p=0.99). The mice were injected with Δ4A (100 μg/day), Δ4A plus letrozole (10 μg/day), entinostat (2.5 mg/kg/day), entinostat plus Δ4A, entinostat plus Δ4A plus letrozole or vehicle. The mice were injected 5 times a week. The tumors were measured every week with calipers and the tumor volumes were calculated using formula, 4/3 π r12r2. The mice in the entinostat plus Δ4A plus letrozole group had the least tumor growth rate (0.004+0.081), which was lower than entinostat plus Δ4A (0.115+0.079) and Δ4A plus letrozole (0.096+0.080). This data suggests a trend towards improved inhibition of tumor growth with combination of entinostat plus letrozole. The mice were sacrificed on week 9 due to large tumor volumes. The tumors and uteri were excised, cleaned, weighed and stored for additional analysis.
 In addition, ability of this combination to inhibit migration in vitro was examined by wound healing assay. The combination of entinostat plus letrozole provides superior inhibition of migration (p<0.001) compared to control, entinostat and letrozole alone. This suggests that the combination of entinostat plus letrozole has potential of inhibiting metastatic spread along with tumor growth.
 These findings indicate that ERα in ER- breast cancer cells is silenced along with aromatase but can be restored with HDACi. Thus activation of silenced ER and intratumoral aromatase by HDACi could open a new avenue for management of ER- advanced breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6128.