Abstract P6-04-23: Targeting of endocrine therapy resistance through combined mTOR and histone deacetylase inhibition

Abstract

Abstract Background: Primary and acquired resistance to endocrine therapy in advanced breast cancer presents a significant barrier to maximizing the clinical effectiveness of these agents. Preclinical data has demonstrated that up-regulation and/or constitutive activation of estrogen independent growth signaling pathways drive resistance to aromatase inhibitors and that targeting of these pathways is an effective strategy to overcoming the resistance. We recently reported in a randomized, placebo controlled phase 2 study that entinostat (ENT), an oral class 1 selective HDAC inhibitor, combined with exemestane extended PFS and OS in postmenopausal women with ER+ positive breast cancer that had progressed on a prior nonsteroidal aromatase inhibitor. Likewise, everolimus (EVE), a mTORi, combined with exemestane or tamoxifen (TAM) also significantly extended PFS in a similar patient population. In order to determine the potential benefit of combining ENT with EVE plus hormone therapy we have piloted a series of xenograft studies in primary human tumor models of TAM sensitivity and resistance. Methods: Athymic nude mice bearing xenografts of tissue derived directly from patient tumors (MaCa4049 – TAM sensitive; MaCa3366/TAM – partially resistant to TAM) were treated with A) vehicle B) 2 mg/kg EVE C) 2 mg/kg EVE + 10 mg/kg TAM D) 15 mg/kg ENT E) 2mg/kg EVE + 10mg/kg TAM + 15 mg/kg ENT. Tumor samples taken at the end of the study were cryoconserved for analysis of gene and protein expression and protein phosphorylation. Results: Growth of MaCa4049 tumors was inhibited in all treatment groups relative to vehicle in two independent studies conducted in this tumor model. Groups B, C and D demonstrated a similar level of activity while maximal inhibition was observed in Group E (combination of EVE + ENT + TAM). All treatments were generally well tolerated with weight loss similar in groups C and E. Treatment of MaCa3366/TAM tumors resulted in similar levels of tumor growth inhibition in groups B, C and E which were all highly effective in suppressing tumor growth in this model. As EVE alone was highly effective as a single agent in the MaCa3366/TAM model the contribution of ENT will be assessed through molecular analysis of tumors upon study completion. Efficacy results and analysis of tumor samples from completed studies will be presented to provide insight into mechanism of action for the triple combination. Conclusions: Preclinical data demonstrating enhanced activity of entinostat combined with everolimus and hormone therapy provides the rationale for clinical investigation of this novel therapeutic approach to targeting hormone therapy resistance. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-23.