美国发现雌激素受体阳性乳腺癌新药
雌激素受体阳性乳腺癌是最常见的乳腺癌类型,通常对内分泌治疗有效,如果发生耐药和远处转移,目前无法治愈。
2021年7月21日,美国科学促进会《科学》旗下《转化医学》在线发表伊利诺伊大学厄巴纳总校、芝加哥大学、范德堡大学英格拉姆癌症中心、伊利诺伊大学芝加哥分校、芝加哥洛约拉大学的研究报告,发现小分子化合物ErSO可激活未折叠蛋白反应,诱发雌激素受体阳性乳腺癌消退且不复发。
首先,该研究发现ErSO可在体外激活未折叠蛋白反应并诱发雌激素受体阳性乳腺癌细胞系快速且有选择性地坏死。
随后,该研究在携带不同人类乳腺癌细胞系或患者来源异种移植乳腺肿瘤的临床前乳腺癌原位和转移小鼠模型体内对ErSO进行测试。
对于乳腺癌原位模型,口服或向腹膜内注射ErSO治疗14~21天可诱发肿瘤消退且不复发。
对于乳腺癌转移模型,ErSO还可有效诱发大多数肺、骨、肝转移灶消退。对于携带颅内人类乳腺癌细胞系异种移植小鼠,ErSO治疗可诱发脑转移灶几乎完全消退。
未完全消退和重新生长的肿瘤对ErSO再治疗仍然敏感。
即使ErSO的剂量高于治疗效果所需,小鼠、大鼠和犬的耐受性仍然良好,并且对雌激素受体表达正常的小鼠组织几乎没有影响。
因此,该研究结果表明,ErSO通过激活未折叠蛋白反应肿瘤保护途径可产生诱导肿瘤消退的抗癌作用,故有必要进一步对人类开展临床研究进行验证。
Sci Transl Med. 2021 Jul 21;13(603):eabf1383.
A small-molecule activator of the unfolded protein response eradicates human breast tumors in mice.
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 M. 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.
University of Illinois at Urbana-Champaign, Urbana, IL, USA; University of Chicago, Chicago, IL, USA; Systems Oncology, Scottsdale, AZ, USA; Vanderbilt Ingram Cancer Center, Nashville, TN, USA; University of Illinois at Chicago, Chicago, IL, USA; Loyola University Chicago, Maywood, IL, USA.
Beating back breast cancer: Estrogen receptor-positive breast cancer is the most common type of breast cancer and, in its metastatic form, is currently incurable. In a new study, Boudreau et al. describe a compound, ErSO, that can activate the unfolded protein response, resulting in necrosis of human breast cancer cell lines in vitro. In vivo, this treatment induced complete regression of cell line and patient-derived orthotopic and metastatic breast cancer xenografts in mice. The authors showed that this treatment was well tolerated in mice, rats, and dogs and could provide a new avenue of intervention for this deadly disease.
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.
DOI: 10.1126/scitranslmed.abf1383