Dallas/Fort Worth Living Legend Chair of Cancer Research, Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Ann Surg Oncol. 2019 Jul;26(7):1981-1990. doi: 10.1245/s10434-019-07291-1. Epub 2019 Mar 25.
The discovery of nonsteroidal antiestrogens created a new group of medicines looking for an application; however, at the time, cytotoxic chemotherapy was the modality of choice to treat all cancers. Antiestrogens were orphan drugs until 1971, with the passing of the National Cancer Act. This enabled laboratory innovations to aid patient care.
This article traces the strategic application of tamoxifen to treat breast cancer by targeting the estrogen receptor (ER), deploying long-term adjuvant tamoxifen therapy, and becoming the first chemopreventive for any cancer. Laboratory discoveries from the University of Wisconsin Comprehensive Cancer Center (UWCCC) are described that address a broad range of biological issues with tamoxifen. These translated to improvements in clinical care.
Tamoxifen was studied extensively at UWCCC in the 1980s for the development of acquired resistance to long-term therapy. Additionally, the long-term metabolism of tamoxifen and regulation of growth factors were also studied. A concern with tamoxifen use for chemoprevention was that an antiestrogen would increase bone loss and atherosclerosis. Laboratory studies with tamoxifen and keoxifene (subsequently named raloxifene) demonstrated that 'nonsteroidal antiestrogens' maintained bone density, and this translated into successful clinical trials with tamoxifen at UWCCC. However, tamoxifen also increased endometrial cancer growth; this discovery in the laboratory translated into changes in clinical care. Selective estrogen receptor modulators (SERMs) were born at UWCCC.
There are now five US FDA-approved SERMs, all with discovery origins at UWCCC. Women's health was revolutionized as SERMs have the ability to treat multiple diseases by switching target sites around a woman's body on or off.
非甾体类抗雌激素的发现开创了新药研发领域的一个全新方向；然而，当时细胞毒性化疗是治疗所有癌症的首选方法。直到 1971 年《国家癌症法案》通过，抗雌激素才成为孤儿药，这使得实验室创新能够帮助患者治疗。
本文通过靶向雌激素受体（ER）来追踪他莫昔芬治疗乳腺癌的战略应用，采用长期辅助他莫昔芬治疗，并成为第一种用于任何癌症的化学预防药物。文中描述了威斯康星大学综合癌症中心（UWCCC）的实验室发现，这些发现解决了他莫昔芬的广泛生物学问题，并转化为临床护理的改进。
在 20 世纪 80 年代，UWCCC 对他莫昔芬进行了广泛研究，以开发对长期治疗的获得性耐药。此外，还研究了他莫昔芬的长期代谢和生长因子的调节。人们担心他莫昔芬用于化学预防会增加骨质流失和动脉粥样硬化。用他莫昔芬和 keoxifene（后命名为雷洛昔芬）进行的实验室研究表明，“非甾体类抗雌激素”可以保持骨密度，这一发现转化为 UWCCC 成功的他莫昔芬临床试验。然而，他莫昔芬也会增加子宫内膜癌的生长；这一实验室发现转化为临床护理的改变。选择性雌激素受体调节剂（SERMs）在 UWCCC 诞生。
现在有五种美国食品和药物管理局批准的 SERMs，全部源自 UWCCC。由于 SERMs 具有通过在女性体内打开或关闭靶标部位来治疗多种疾病的能力，因此女性健康得到了革命性的改变。
