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A small-molecule activator of the unfolded protein response eradicates human breast tumors in mice
Science Translational Medicine ( IF 17.1 ) Pub Date : 2021-07-21 , DOI: 10.1126/scitranslmed.abf1383
Matthew W Boudreau 1, 2 , Darjan Duraki 3 , Lawrence Wang 3 , Chengjian Mao 3 , Ji Eun Kim 3 , Madeline A Henn 4 , Bingtao Tang 4 , Sean W Fanning 5 , Jeffrey Kiefer 6 , Theodore M Tarasow 6 , Elizabeth M Bruckheimer 6 , Ramon Moreno 6 , Spyro Mousses 6 , Geoffrey L Greene 5 , Edward J Roy 4, 7 , Ben Ho Park 8 , Timothy M Fan 2, 4, 7, 9 , Erik R Nelson 2, 4, 7, 10, 11 , Paul J Hergenrother 1, 2, 7 , David J Shapiro 3, 7
Affiliation  

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.



中文翻译:

未折叠蛋白反应的小分子激活剂可根除小鼠的人乳腺肿瘤

转移性雌激素受体α(ERα)阳性乳腺癌目前无法治愈。为了针对这些耐药性癌症,我们报告了一种名为 ErSO 的化合物的发现,该化合物可在体外激活预期的未折叠蛋白反应 (a-UPR) 并诱导 ERα 阳性乳腺癌细胞系的快速和选择性坏死。然后,我们在几个携带不同异种移植的人乳腺癌系或患者来源的乳腺肿瘤的临床前原位和转移小鼠模型中在体内测试了 ErSO。在多个原位模型中,口服或腹腔内给予 ErSO 治疗 14 至 21 天诱导肿瘤消退而没有复发。在细胞系尾静脉转移模型中,ErSO 还有效诱导大多数肺、骨和肝转移瘤的消退。ErSO 治疗诱导携带颅内人乳腺癌细胞系异种移植物的小鼠的脑转移几乎完全消退。未经历完全消退和再生长的肿瘤对用 ErSO 再治疗仍然敏感。ErSO 在小鼠、大鼠和狗中以高于治疗反应所需的剂量耐受良好,并且对正常表达 ERα 的小鼠组织几乎没有影响或没有影响。ErSO 通过激活 a-UPR 介导其抗癌作用,表明激活肿瘤保护途径可诱导肿瘤消退。和狗的剂量高于治疗反应所需的剂量,对正常表达 ERα 的鼠组织几乎没有影响或没有影响。ErSO 通过激活 a-UPR 介导其抗癌作用,表明激活肿瘤保护途径可诱导肿瘤消退。和狗的剂量高于治疗反应所需的剂量,对正常表达 ERα 的鼠组织几乎没有影响或没有影响。ErSO 通过激活 a-UPR 介导其抗癌作用,表明激活肿瘤保护途径可诱导肿瘤消退。

更新日期:2021-07-22
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