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. 2025 Feb;32(2):417-427.
doi: 10.1007/s43032-024-01775-6. Epub 2024 Dec 29.

Evaluation of the In Vivo Efficacy of the JAK Inhibitor AZD1480 in Uterine Leiomyomas Using a Patient-derived Xenograft Murine Model

Michael F Neblett 2nd  1   2 , Merrick T Ducharme  2 , Jeffrey A Meridew  3 , Andrew J Haak  3 , Sylvie Girard  1   2   4 , Daniel J Tschumperlin  2   3 , Elizabeth A Stewart  5   6   7
Affiliations

Evaluation of the In Vivo Efficacy of the JAK Inhibitor AZD1480 in Uterine Leiomyomas Using a Patient-derived Xenograft Murine Model

Michael F Neblett 2nd et al. Reprod Sci. 2025 Feb.

Abstract

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.

Keywords: AZD1480; JAK/STAT; Leiomyoma; Patient-derived; Treatment; Xenograft.

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Conflict of interest statement

Declarations. EAS has received grants for her institution from the Agency for Healthcare Research and Quality/Patient-Centered Outcome Research (P50HS23418), and the Eunice Kennedy Shriver Institute of Child Health and Human Development of the National Institutes of Health (R01HD105714, R01HD109127-01A1 and P50HD115283); has received consulting fees from AbbVie, Anylyn; support for service on a DSMB from Myovant, holds a patent for Methods and Compounds for Treatment of Abnormal Uterine Bleeding; has received royalties from UpToDate; has received fees for developing educational content from the MED-IQ, Physicians’ Education Resource, Omnia Education, Omnicuris and WebMD; and serves as an unpaid advisor to The Fibroid Foundation and the unpaid treasurer of the International Gynecologic Society. The remaining authors report no conflict of interest.

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