Abstract P5-09-20: Development of a novel selective estrogen receptor down-regulator which shows efficacy in pre-clinical models of endocrine resistance

With over 70% of breast cancers expressing the estrogen receptor alpha (ERa), treatment with either anti-hormonal therapies that directly block ER function (e.g.Tamoxifen) or therapies that block the production of estrogen itself (e.g. aromatase inhibitors) are key to management of the disease. Despite initial efficacy seen with endocrine therapies, development of either de novo or acquired resistance ultimately limits the use of these agents although the majority of tumours continue to depend on ERα for growth. The ability to down regulate ER is particularly important in the endocrine resistance setting where ER appears to be activated in a ligand independent fashion by other growth factor signaling pathways. Agents such as Fulvestrant have been shown to offer additional benefit in the advanced setting due to its unique mechanism of binding and degradation of the ER receptor by the ubiquitin-proteosome complex. Given its low level of bioavailability and metabolic profile, Fulvestrant has been formulated as an intramuscular injection with 2 × 250mg monthly doses currently being tested clinically. We have sought to identify a novel, non-steroidal ERα antagonist and down-regulator that can be administered orally and could yield improved bioavailability and clinical benefit through enhanced biomarker modulation. We have identified a novel compound that can induce ERα degradation in breast cancer cell lines at picomolar concentrations with a similar half-life to Fulvestrant and is clearly differentiated from Tamoxifen which appears to stabilise ER protein. Due to good oral pharmacokinetic properties of the compound we have seen significant tumour efficacy in both tamoxifen-sensitive and -resistant models of breast cancer in vivo. In an MCF-7 model we have shown >90% reduction in PR levels in a pharmacodynamic study and complete tumour growth inhibition (TGI) at 5mg/kg dose. Fulvestrant in the same model setting was unable to achieve >60% PR inhibition at dose levels 3.8 fold greater than those achieved clinically with 500mg. We have also seen tumour regressions in a pre-clinical long term estrogen deprived (LTED) model, which mimic the aromatase resistance setting, and efficacy correlates with a significant decrease in ERα levels (>60%). This orally bioavailable compound is progressing towards clinical evaluation and shows promise as a new SERD agent for the treatment of ER+ breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-09-20.