PO.TB03.01 · 肿瘤生物学
拉索昔芬是雌激素受体阳性乳腺癌的一种保护骨骼的治疗选择
Lasofoxifene is a bone protective treatment option for estrogen receptor positive breast cancers
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
雌激素受体阳性（ER+）乳腺癌主要转移至骨微环境，ER+疾病患者发生骨转移的可能性几乎是其他亚型患者的两倍。当前内分泌治疗常导致骨质疏松症及随后的骨转换，这可能加速转移进展。这凸显了对同时抑制肿瘤生长并保护骨微环境的新型治疗的需求。芳香化酶抑制剂和ER拮抗剂（如氟维司群）等标准治疗在乳腺和骨骼中均无差别地抑制ER信号传导。拉索昔芬是一种选择性ER调节剂，在骨骼中表现出组织选择性的ER激动活性，目前正在ELAINE-III临床试验[NCT05696626]中与abemaciclib联合评估，用于治疗ESR1突变的晚期或转移性ER+乳腺癌。在此，我们研究了拉索昔芬骨选择性ER激动活性的生理相关性及其对转移进展的影响。用拉索昔芬或标准内分泌治疗处理卵巢切除诱导的骨质疏松症动物模型，并通过组织学和显微CT组织形态计量学分析股骨。同时，在临床相关的内分泌治疗敏感和耐药的原发及转移性患者来源异种移植（PDX）模型中，评估拉索昔芬在体外和体内的抗肿瘤作用。此外，进行了拉索昔芬与NCI NExT Oncology Interrogation Tools套件（含555种药物）的药物协同研究，鉴定出在拉索昔芬处理的细胞中易受药理学抑制的通路。我们发现拉索昔芬可防止激素撤退诱导的骨丢失，并在ER+乳腺癌的原发和转移模型中维持强健的抗肿瘤应答。药物协同筛选确定了与拉索昔芬合理联合以进一步增强其抗肿瘤活性的选择。总体而言，本研究支持使用基于拉索昔芬的治疗组合，以在抑制骨龛中ER+转移进展的同时保护骨结构。
查看英文原文 English abstract
Estrogen receptor positive (ER+) breast cancer primarily metastasizes to the bone microenvironment, and patients with ER+ disease are almost twice as likely to develop bone metastasis as those with other subtypes. Treatment with current endocrine therapies frequently results in osteoporosis and subsequent bone turnover which can potentially accelerate metastatic progression. This underscores the need for new treatments which will simultaneously inhibit tumor growth and preserve the bone microenvironment. Standard treatments like aromatase inhibitors and ER-antagonists, like fulvestrant, indiscriminately suppress ER signaling, in both breast and bone. Lasofoxifene, a selective ER modulator, exhibits tissue-selective ER-agonist activity in bone and is currently being evaluated in the ELAINE-III clinical trial [NCT05696626] in combination with abemaciclib for the treatment of ESR1-mutant advanced or metastatic ER+ breast cancer. Here, we investigated the physiological relevance of lasofoxifene's bone-selective ER-agonist activity and its impact on metastatic progression. Animal models of ovariectomy-induced osteoporosis were treated with lasofoxifene or standard endocrine therapies, and femurs were analyzed by histology and micro-CT histomorphometry. In parallel, anti-tumor effects of lasofoxifene were evaluated in vitro and in vivo in clinically relevant endocrine therapy-sensitive and -resistant primary and metastatic Patient-Derived Xenograft models. Additionally, drug synergism studies with lasofoxifene and the NCI NExT Oncology Interrogation Tools Set of 555 drugs were performed which identified pathways that were vulnerable to pharmacological inhibition in lasofoxifene-treated cells. We found that lasofoxifene protected against hormone withdrawal-induced bone loss and maintained a robust anti-tumor response in primary and metastatic models of ER+ breast cancer. Drug synergy screens have defined choices for rational combination with lasofoxifene to further potentiate its anti-tumor activity. Overall, this study supports the use of lasofoxifene-based treatment combinations which will concurrently protect bone architecture while suppressing ER+ metastasis progression in the bone niche.
利益披露 Disclosure
E. K. Zboril, None..
F. E. Parker, None.