Abstract A4: A novel class of selective ERα degraders acts as full antagonists/ inverse agonists and displays efficacy in pre-clinical models of endocrine-resistant breast cancer and endometrial cancer

Media type: E-Article

Title: Abstract A4: A novel class of selective ERα degraders acts as full antagonists/ inverse agonists and displays efficacy in pre-clinical models of endocrine-resistant breast cancer and endometrial cancer

Contributor: Darimont, Beatrice; Lu, Ninh; Sensintaffar, John; Lee, Kyoung-Jin; Aparicio, Anna; Kaufman, Joshua; Bischoff, Eric; Rix, Peter; Heyman, Rich; Smith, Nicholas; Hager, Jeffrey; Joseph, James; Grillot, Katherine; Qian, Jing; Gang, Shao; Govek, Steven; Nagasawa, Johnny; Lai, Andiliy; Kahraman, Mehmet

imprint: American Association for Cancer Research (AACR), 2012

Language: English

DOI: 10.1158/1078-0432.mechres-a4

ISSN: 1078-0432; 1557-3265

Keywords: Cancer Research ; Oncology

Origination:

Footnote:

Description: Abstract While endocrine therapies are initially effective to treat estrogen receptor (ERα) positive breast cancer tumors, acquired resistance invariably emerges. Although resistant tumors typically display changes in PI3K or other kinase pathways, the majority of these tumors continue to express and depend on ERα for growth and survival. Exploring the hypothesis that endocrine resistance might involve hormone-independent activities of ERα, we have developed two distinct classes of potent, non-steroidal ERα modulators that antagonize hormone-mediated transcriptional activities of ER and lower ERα steady state levels. These compounds showed robust efficacy in pre-clinical models of endocrine-resistant breast cancer, including some with up-regulated PI3K pathways. In contrast to their activity as full antagonists/ inverse agonists in the breast, the two classes of ERα modulators displayed distinct abilities to oppose the activity of estradiol in the uterine endometrium, another well-characterized ERα target tissue. Similar to endocrine-resistant breast cancer, a large percentage of endometrial cancers have altered PI3K pathways and typically respond poorly to endocrine therapy. In mouse xenograft models one of our compounds inhibited the growth of ECC-1 endometrial cancer tumors with substantially higher efficacy than the selective ER modulator arzoxifene, which in a phase II clinical trial exhibited a 30% response rate in patients with recurring ERα-positive endometrial cancers. Hence, beyond their promise as a next generation therapy for the treatment of endocrine resistant ER+ breast cancer, these novel classes of selective estrogen receptor degraders might also open new opportunities for endocrine therapies targeting endometrial cancer.

Access State: Open Access

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