nintedanib and Uterine-Neoplasms

Uterine fibroids are highly prevalent, collagen-rich, mechanically stiff, fibrotic tumors for which new therapeutic options are needed. Increased extracellular matrix (ECM) stiffness activates mechanical signaling and Hippo/YAP promoting fibroid growth, but no prior studies have tested either as a therapeutic target. We tested the hypothesis that injection of a purified form of collagenase Clostridium histolyticum (CCH) that selectively digests type I and type III collagens would alter ECM stiffness, Hippo signaling, and selectively reduce fibroid cell growth. We also used two FDA-approved drugs, verteporfin and nintedanib, to elucidate the role of Hippo/YAP signaling in uterine fibroid and myometrial cells.. The clinical trial was registered (NCT02889848). Stiffness of samples was measured by rheometry. Protein expression in surgical samples was analyzed via immunofluorescence. Protein and gene expression in uterine fibroid or myometrial cell lines were measured by real time PCR and western blot, and immunofluorescence.. Injection of CCH at high doses (0.1-0.2 mg/cm. This is the first report that in vivo injection of collagenase into uterine fibroids led to a reduction in Hippo/YAP signaling and crucial genes and pathways involved in fibroid growth. These results indicate that targeting ECM stiffness and Hippo signaling might be an effective strategy for uterine fibroids.

Topics: Activin Receptors, Type II; Adult; Antifibrotic Agents; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Extracellular Matrix; Female; Hippo Signaling Pathway; Humans; Indoles; Integrin beta1; Leiomyoma; Microbial Collagenase; Middle Aged; Smad2 Protein; Transcription Factors; Uterine Neoplasms; Verteporfin