Abstract P5-05-02: Preclinical development of OP-1250, an oral complete estrogen receptor antagonist (CERAN) that shrinks ER-positive breast tumors in xenograft models
Authors: Hodges-Gallagher Leslie , Sun Richard , Myles David C , Harmon Cyrus L , Kushner Peter J 
Published: March 2020

Abstract
Fulvestrant (FASLODEX) is the most effective endocrine therapy for estrogen receptor positive (ER+) metastatic breast cancer (MBC). Despite this superiority, fulvestrant must be delivered by intramuscular injection and its efficacy appears limited by poor drug exposure. Thus, an oral compound that shares fulvestrant’s pharmacodynamic virtues with improved drug exposure might be both more convenient and more effective than fulvestrant. Fulvestrant development was aimed at creating a Complete Estrogen Receptor ANtagonist (CERAN) using the rodent uterine weight gain assay. It is now understood that the ability of fulvestrant to shut off both the AF1 and AF2 transcriptional activation functions of the ER underlies this activity. In contrast to CERANs, selective estrogen receptor modulators (SERMs) such as tamoxifen efficiently shut off AF2 signaling (turned on by estradiol), but incompletely antagonize AF1, a function that is turned on by multiple cell signaling pathways and shown to play a role in the development of endocrine resistance. We have developed a sensitive cell culture assay that distinguish between CERANs and SERMs. Fulvestrant is also a Selective Estrogen Receptor Degrader (SERD), and it has become widely but mistakenly assumed that such ability makes a compound a CERAN. In our assay several SERDs under clinical investigation, including AZD9496 and GDC-0810, were identified as SERMs that exhibited ER-mediated agonism on genes dependent on AF1 activity. Further, these SERM/SERDs stimulate cell proliferation of CAMA-1 and HCC-1500 breast cancer cells even in the absence of estrogen. These proliferation assays may model clinical breast cancer progression in which tumors become less dependent on estrogen and more sensitive to AF1 signaling mediated by SRC family kinases, IGFs, and FGFs. We thus predict that SERM/SERDs will be inferior in preventing and treating resistance compared to CERAN/SERDs.
Guided by our cell culture assay, we have developed the CERAN/SERD OP-1250. OP-1250 completely blocks both AF2 and AF1 activity as seen in cell culture and the ovex mouse uterine weight gain assay. Unlike SERM/SERDs, OP-1250 is a potent inhibitor of CAMA1 and HCC-1500 breast cancer cell proliferation. OP-1250 also is a SERD in a large variety of cell lines including those in which some SERM/SERDs have little activity. OP-1250 achieves high and stable drug exposure in multiple animal species unlike fulvestrant and many SERMs. As might be expected for a compound with this spectrum of activities, OP-1250 shrinks tumors in xenograft models in which fulvestrant (because of limited drug exposure) and SERM/SERDs (because of residual estrogen-like action) fail to shrink the tumors. These models include HCC-1500 xenografts with a wild type ER and HCI-013 patient-derived xenografts with ESR1Y537S. These results suggest that OP-1250 has potential to be a superior compound to treat ER+ MBC, especially in patients whose tumors allow high activity of AF1 and including those with activating mutations ins ESR1. We expect to bring OP-1250 into the clinic shortly.
Citation Format: Leslie Hodges-Gallagher, Richard Sun, David C Myles, Cyrus L Harmon, Peter J Kushner. Preclinical development of OP-1250, an oral complete estrogen receptor antagonist (CERAN) that shrinks ER-positive breast tumors in xenograft models [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-05-02.