Garner Fiona, Shomali Maysoun, Paquin Dotty, Lyttle C Richard, Hattersley Gary
aRadius Health Inc., Waltham bPfizer, Andover, Massachusetts, USA.
Anticancer Drugs. 2015 Oct;26(9):948-56. doi: 10.1097/CAD.0000000000000271.
Agents that inhibit estrogen production, such as aromatase inhibitors or those that directly block estrogen receptor (ER) activity, such as selective estrogen receptor modulators and selective estrogen receptor degraders, are routinely used in the treatment of ER-positive breast cancers. However, although initial treatment with these agents is often successful, many women eventually relapse with drug-resistant breast cancers. To overcome some of the challenges associated with current endocrine therapies and to combat the development of resistance, there is a need for more durable and more effective ER-targeted therapies. Here we describe and characterize a novel, orally bioavailable small-molecule selective estrogen receptor degrader, RAD1901, and evaluate its therapeutic potential for the treatment of breast cancer. RAD1901 selectively binds to and degrades the ER and is a potent antagonist of ER-positive breast cancer cell proliferation. Importantly, RAD1901 produced a robust and profound inhibition of tumor growth in MCF-7 xenograft models. In an intracranial MCF-7 model, RAD1901-treated animals survived longer than those treated with either control or fulvestrant, suggesting the potential benefit of RAD1901 in the treatment of ER-positive breast cancer that has metastasized to the brain. Finally, RAD1901 preserved ovariectomy-induced bone loss and prevented the uterotropic effects of E2, suggesting that it may act selectively as an agonist in bone but as an antagonist in breast and uterine tissues. RAD1901 is currently under clinical study in postmenopausal women with ER-positive advanced breast cancer.
抑制雌激素生成的药物，如芳香化酶抑制剂，或直接阻断雌激素受体（ER）活性的药物，如选择性雌激素受体调节剂和选择性雌激素受体降解剂，常用于治疗ER阳性乳腺癌。然而，尽管这些药物的初始治疗往往成功，但许多女性最终会复发为耐药性乳腺癌。为了克服当前内分泌治疗相关的一些挑战并对抗耐药性的发展，需要更持久、更有效的ER靶向治疗。在此，我们描述并表征了一种新型的、口服生物可利用的小分子选择性雌激素受体降解剂RAD1901，并评估其治疗乳腺癌的潜力。RAD1901选择性地结合并降解ER，是ER阳性乳腺癌细胞增殖的有效拮抗剂。重要的是，RAD1901在MCF-7异种移植模型中对肿瘤生长产生了强大而深刻的抑制作用。在颅内MCF-7模型中，接受RAD1901治疗的动物比接受对照或氟维司群治疗的动物存活时间更长，这表明RAD1901在治疗已转移至脑部的ER阳性乳腺癌方面具有潜在益处。最后，RAD1901保留了卵巢切除诱导的骨质流失，并预防了E2的子宫促生长作用，这表明它可能在骨骼中选择性地作为激动剂起作用，但在乳腺和子宫组织中作为拮抗剂起作用。RAD1901目前正在绝经后ER阳性晚期乳腺癌女性中进行临床研究。
