Laser-assisted topical delivery of vismodegib reduces hedgehog gene expression in human basal cell carcinomas in vivo.

Autor: Olesen UH; Department of Dermatology, Copenhagen University Hospital-Bispebjerg, Copenhagen, Denmark., Pedersen KK; Department of Dermatology, Copenhagen University Hospital-Bispebjerg, Copenhagen, Denmark., Togsverd-Bo K; Department of Dermatology, Copenhagen University Hospital-Bispebjerg, Copenhagen, Denmark., Biskup E; Department of Pathology, Copenhagen University Hospital-Herlev, Herlev, Denmark., Nielsen AL; Department of Oncology, Copenhagen University Hospital-Herlev, Herlev, Denmark., Jackerott M; Leo Pharma A/S, Ballerup, Denmark., Clergeaud G; Department of Health Technology, Technical University of Denmark, Lyngby, Denmark., Andresen TL; Department of Health Technology, Technical University of Denmark, Lyngby, Denmark., Haedersdal M; Department of Dermatology, Copenhagen University Hospital-Bispebjerg, Copenhagen, Denmark.; Department of Clinical Medicine, Copenhagen University, Copenhagen, Denmark.
Jazyk: angličtina
Zdroj: Lasers in surgery and medicine [Lasers Surg Med] 2024 Mar; Vol. 56 (3), pp. 239-248. Date of Electronic Publication: 2024 Feb 04.
DOI: 10.1002/lsm.23766
Abstrakt: Background: Systemically delivered hedgehog inhibitors including vismodegib and sonidegib are widely used to treat basal cell carcinomas (BCCs). Ablative fractional laser (AFL)-assisted topical delivery of vismodegib has been demonstrated in preclinical studies. The aim of this explorative clinical study was to evaluate intratumoral vismodegib concentrations and effect on hedgehog pathway gene expression following AFL-assisted topical vismodegib delivery to BCCs.
Methods: In an open-label clinical trial, 16 nodular BCCs (in n = 9 patients) received one application of CO 2 -AFL (40 mJ/microbeam, 10% density) followed by topical vismodegib emulsion. After 3-4 days, vismodegib concentrations in tumor biopsies (n = 15) and plasma were analyzed and compared with samples from patients receiving oral treatment (n = 3). GLI1, GLI2, PTCH1, and PTCH2 expression was determined by quantitative polymerase chain reaction (n = 7) and GLI1 additionally by in situ hybridization (n = 3).
Results: Following AFL-assisted topical administration, vismodegib was detected in 14/15 BCCs and reached a median concentration of 6.2 µmol/L, which compared to concentrations in BCC tissue from patients receiving oral vismodegib (9.5 µmol/L, n = 3, p = 0.8588). Topical vismodegib reduced intratumoral GLI1 expression by 51%, GLI2 by 55%, PTCH1 and PTCH2 each by 73% (p ≤ 0.0304) regardless of vismodegib concentrations (p ≥ 0.3164). In situ hybridization demonstrated that GLI1 expression was restricted to tumor tissue and downregulated in response to vismodegib exposure.
Conclusion: A single AFL-assisted topical application of vismodegib resulted in clinically relevant intratumoral drug concentrations and significant reductions in hedgehog pathway gene expressions.
(© 2024 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals LLC.)
Databáze: MEDLINE
Externí odkaz: