Neblett Michael F, Ducharme Merrick T, Meridew Jeffrey A, Haak Andrew J, Girard Sylvie, Tschumperlin Daniel J, Stewart Elizabeth A
Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, USA.
Mayo Clinic Alix School of Medicine, Rochester, MN, USA.
Reprod Sci. 2025 Feb;32(2):417-427. doi: 10.1007/s43032-024-01775-6. Epub 2024 Dec 29.
Uterine leiomyomas are common noncancerous hormonally-dependent neoplasms comprised of uterine smooth-muscle cells and fibroblasts. Despite their significant impact on morbidity, effective non-hormonal medical treatments are lacking. In vitro studies have identified the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway as a promising target in leiomyoma cells. Our objective was to evaluate the efficacy of AZD1480, a JAK 1/2 inhibitor, in treating uterine leiomyomas using a patient-derived xenograft murine model. Ovariectomized immunodeficient mice received an estrogen and progesterone pellet and were subsequently implanted with human leiomyoma tissue surgically resected from premenopausal women not on hormonal medication. Mice were divided into treatment (n = 6) and vehicle control (n = 6) groups receiving either 50 mg/kg of AZD1480 or vehicle via oral gavage for 5 days/week for 28 days. Our results demonstrate a significant AZD1480-mediated reduction in both xenograft volume (59.5% vs. 0.3%; treated vs. control, p < .0001) and weight (56.0% vs. 31.2%; p = 0.03) compared to controls. Moreover, xenografts from the treated group exhibited a significant decrease in cell density(p = 0.01). Levels of pSTAT3-positive cells (4.1% vs. 10.3%), Ki67-positive cells (4.1% vs. 6.5%), and fibrillar collagen (19.8% vs. 29.5%) declined but did not reach statistical significance, whereas AZD1480 treatment significantly reduced blood vessel formation in the xenografts (20.1 vs 45.6 per FOV; p = 0.01). These findings suggest JAK inhibition as a potential treatment for uterine leiomyomas by targeting angiogenesis. However, further studies are warranted to explore alternative JAK inhibitors, examine downstream effects, optimize dosing, and establish clinical efficacy and safety.
子宫平滑肌瘤是常见的非癌性激素依赖性肿瘤，由子宫平滑肌细胞和成纤维细胞组成。尽管它们对发病率有重大影响，但缺乏有效的非激素药物治疗方法。体外研究已确定 Janus 激酶/信号转导子和转录激活子（JAK/STAT）信号通路是平滑肌瘤细胞中有前景的治疗靶点。我们的目的是使用患者来源的异种移植小鼠模型评估 JAK 1/2 抑制剂 AZD1480 治疗子宫平滑肌瘤的疗效。去卵巢的免疫缺陷小鼠接受雌激素和孕酮缓释丸，随后植入从未接受激素治疗的绝经前妇女手术切除的人平滑肌瘤组织。将小鼠分为治疗组（n = 6）和载体对照组（n = 6），分别通过口服灌胃给予 50 mg/kg 的 AZD1480 或载体，每周 5 天，共 28 天。我们的结果表明，与对照组相比，AZD1480 介导的异种移植物体积（59.5% 对 0.3%；治疗组对对照组，p < 0.0001）和重量（56.0% 对 31.2%；p = 0.03）均显著降低。此外，治疗组的异种移植物细胞密度显著降低（p = 0.01）。pSTAT3 阳性细胞（4.1% 对 10.3%）、Ki67 阳性细胞（4.1% 对 6.5%）和纤维状胶原蛋白（19.8% 对 29.5%）水平下降，但未达到统计学意义，而 AZD1480 治疗显著减少了异种移植物中的血管形成（每个视野 20.1 对 45.6；p = 0.01）。这些发现表明，通过靶向血管生成，JAK 抑制可能是治疗子宫平滑肌瘤的一种方法。然而，有必要进一步研究以探索其他 JAK 抑制剂，研究下游效应，优化给药方案，并确定临床疗效和安全性。
