Abstract A37: A novel class of selective estrogen receptor degraders display activity in pre-clinical models of ERα+ ovarian cancer
Authors: Joseph James D. , Darimont Beatrice , Govek Steven , Brigham Dan , Aparicio Anna , Kahraman Mehmet , Lai Andiliy , Lee Kyoung-Jin , Lu Nhin , Nagasawa Johnny , Kaufman Josh , Moon Michael , Prudente Rene , Qian Jing , Sensintaffar John , Shao Gang , Rix Peter , Smith Nick , Hager Jeff 
Published: August 2014

Abstract
Greater than 50% of high grade serous ovarian cancers express the estrogen receptor alpha (ERα). This observation, in addition to multiple lines of epidemiological and preclinical data, suggests that, similar to breast and endometrial cancer, estrogen receptor signaling may play a role in the development and progression of ovarian cancer. Unfortunately, unlike in breast cancer, therapeutically targeting ERα signaling in patients with recurrent ovarian cancer typically yields only marginal clinical responses. However, patient selection based solely on ERα expression increases the response rate of aromatase inhibitors suggesting that ERα may be a viable therapeutic target in a subset of ovarian cancer patients. Given the presentation of late-stage disease, the mutational complexity and alteration of multiple signaling pathways known to induce ligand independent ERα activity in ovarian cancer, additional levels of patient stratification as well as novel therapeutics that target both the ligand dependent and independent ERα signaling, have the potential to yield better therapeutic outcomes.
We have identified novel, orally bioavailable non-steroidal ERα antagonists that induce ERα degradation at picomolar concentrations in vitro resulting in significant reduction in steady state ERα protein levels in multiple cancer cell lines. Using peptide-based conformational profiling, we show that these ligands induce estrogen receptor conformations that are distinct from both fulvestrant and tamoxifen indicating novel mechanism of action. Importantly, these compounds block the growth of tamoxifen-sensitive and -resistant models of breast cancer and endometrial cancer in vivo. Similar to the breast and endometrial cancer models, these compounds antagonize ER target gene expression and induce ERα degradation in two ER+ ovarian cancer cell lines, OVSAHO and OVKATE, whereas the first generation ER antagonist tamoxifen antagonizes transcription but stabilizes ERα in this setting. Consistent with their transcriptional antagonist and degrader activities, these compounds also inhibit the hormone-dependent growth of these cell lines in vivo. Based on these findings, these compounds represent a novel class of Selective Estrogen Receptor Degraders (SERDs) that may hold promise as a next generation therapy for the treatment of ER+ ovarian cancer as monotherapy and importantly as combination therapy with agents that target the key nodal points critical to malignant progression or new, emergent agents displaying promising activity.
Citation Format: James D. Joseph, Beatrice Darimont, Steven Govek, Dan Brigham, Anna Aparicio, Mehmet Kahraman, Andiliy Lai, Kyoung-Jin Lee, Nhin Lu, Johnny Nagasawa, Josh Kaufman, Michael Moon, Rene Prudente, Jing Qian, John Sensintaffar, Gang Shao, Peter Rix, Nick Smith, Jeff Hager. A novel class of selective estrogen receptor degraders display activity in pre-clinical models of ERα+ ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A37.