乳腺癌
医学
体内
癌症研究
转移
癌症
激活剂(遗传学)
雌激素受体
内科学
生物
病理
受体
生物技术
作者
Matthew W. Boudreau,Darjan Duraki,Lawrence Wang,Chengjian Mao,Ji Eun Kim,Madeline A. Henn,Bingtao Tang,Sean W. Fanning,Jeffrey Kiefer,Theodore M. Tarasow,Elizabeth Bruckheimer,Ramon Moreno,Spyro Mousses,Geoffrey L. Greene,Edward J. Roy,Ben Ho Park,Timothy M. Fan,Erik R. Nelson,Paul J. Hergenrother,David J. Shapiro
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2021-07-21
卷期号:13 (603)
被引量:20
标识
DOI:10.1126/scitranslmed.abf1383
摘要
Metastatic estrogen receptor α (ERα)-positive breast cancer is presently incurable. Seeking to target these drug-resistant cancers, we report the discovery of a compound, called ErSO, that activates the anticipatory unfolded protein response (a-UPR) and induces rapid and selective necrosis of ERα-positive breast cancer cell lines in vitro. We then tested ErSO in vivo in several preclinical orthotopic and metastasis mouse models carrying different xenografts of human breast cancer lines or patient-derived breast tumors. In multiple orthotopic models, ErSO treatment given either orally or intraperitoneally for 14 to 21 days induced tumor regression without recurrence. In a cell line tail vein metastasis model, ErSO was also effective at inducing regression of most lung, bone, and liver metastases. ErSO treatment induced almost complete regression of brain metastases in mice carrying intracranial human breast cancer cell line xenografts. Tumors that did not undergo complete regression and regrew remained sensitive to retreatment with ErSO. ErSO was well tolerated in mice, rats, and dogs at doses above those needed for therapeutic responses and had little or no effect on normal ERα-expressing murine tissues. ErSO mediated its anticancer effects through activation of the a-UPR, suggesting that activation of a tumor protective pathway could induce tumor regression.
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