In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. P5-08-07-P5-08-07
Abstract:
The human epidermal growth factor receptor 2 (HER2, also known as ERBB2) oncogene is overexpressed in approximately 25% of breast cancer tumors and is associated with a high rate of brain metastasis. Patients with brain metastases have a poor prognosis and limited treatment options available. Since about half of HER2+ tumors are also hormone receptor positive, and cross talk has been shown to occur between these two signaling pathways, it is plausible that these tumors could benefit from the addition of hormonal therapy on top of HER2 inhibition. OP-1250 is a complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD), and has been shown to effectively inhibit estrogen receptor positive (ER+) breast cancer growth in both cell-based assays and xenograft studies. OP-1250 has favorable pharmacokinetic properties and demonstrated brain penetrance in non-clinical models. While extensively characterized in ER+/HER2- breast cancer models, OP-1250 had not previously been tested in a HER2+ context. Here we report OP-1250 inhibited estrogen receptor-driven proliferation and effectively degraded the estrogen receptor in multiple ER+/HER2+ cell lines. OP-1250 combined effectively with HER2 inhibitors tucatinib and trastuzumab, demonstrating that inhibition of both HER2 and estrogen receptor signaling was more effective in inhibiting breast cancer cell proliferation than inhibiting either pathway alone. The addition of OP-1250 to a HER2 inhibitor also resulted in greater tumor shrinkage in multiple ER+/HER2+ xenograft models. Our data suggests a potential clinical benefit in the addition of OP-1250 on top of HER2 inhibition for the treatment of ER+/HER2+ breast cancer and provides strong rationale for a clinical study evaluating the combination of OP-1250 and HER2 targeted agents, which is planned for 2022. Citation Format: Alison D Parisian, Leslie Hodges-Gallagher, Richard Sun, Susanna Barratt, Gopinath S Palanisamy, Julia Lawrence, Pamela Klein, David C Myles, Cyrus L Harmon, Peter J Kushner. The complete estrogen receptor antagonist OP-1250 can combine with HER2 inhibition to inhibit estrogen receptor-driven cellular proliferation and shrink xenograft tumors in ER+/HER2+ breast cancer models [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-08-07.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.SABCS21-P5-08-07
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2022
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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