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

IF 2.2 3区 医学 Q2 DERMATOLOGY
Uffe H. Olesen PhD, Kristian Kåber Pedersen MSc, Katrine Togsverd-Bo PhD, Edyta Biskup PhD, Anni Linnet Nielsen PhD, Malene Jackerott PhD, Gael Clergeaud PhD, Thomas L. Andresen PhD, Merete Haedersdal DMSc
{"title":"Laser-assisted topical delivery of vismodegib reduces hedgehog gene expression in human basal cell carcinomas in vivo","authors":"Uffe H. Olesen PhD,&nbsp;Kristian Kåber Pedersen MSc,&nbsp;Katrine Togsverd-Bo PhD,&nbsp;Edyta Biskup PhD,&nbsp;Anni Linnet Nielsen PhD,&nbsp;Malene Jackerott PhD,&nbsp;Gael Clergeaud PhD,&nbsp;Thomas L. Andresen PhD,&nbsp;Merete Haedersdal DMSc","doi":"10.1002/lsm.23766","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>In an open-label clinical trial, 16 nodular BCCs (in <i>n</i> = 9 patients) received one application of CO<sub>2</sub>-AFL (40 mJ/microbeam, 10% density) followed by topical vismodegib emulsion. After 3–4 days, vismodegib concentrations in tumor biopsies (<i>n</i> = 15) and plasma were analyzed and compared with samples from patients receiving oral treatment (<i>n</i> = 3). GLI1, GLI2, PTCH1, and PTCH2 expression was determined by quantitative polymerase chain reaction (<i>n</i> = 7) and GLI1 additionally by in situ hybridization (<i>n</i> = 3).</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>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, <i>n</i> = 3, <i>p</i> = 0.8588). Topical vismodegib reduced intratumoral GLI1 expression by 51%, GLI2 by 55%, PTCH1 and PTCH2 each by 73% (<i>p</i> ≤ 0.0304) regardless of vismodegib concentrations (<i>p</i> ≥ 0.3164). In situ hybridization demonstrated that GLI1 expression was restricted to tumor tissue and downregulated in response to vismodegib exposure.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>A single AFL-assisted topical application of vismodegib resulted in clinically relevant intratumoral drug concentrations and significant reductions in hedgehog pathway gene expressions.</p>\n </section>\n </div>","PeriodicalId":17961,"journal":{"name":"Lasers in Surgery and Medicine","volume":"56 3","pages":"239-248"},"PeriodicalIF":2.2000,"publicationDate":"2024-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/lsm.23766","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Lasers in Surgery and Medicine","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/lsm.23766","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"DERMATOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

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 CO2-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.

Abstract Image

激光辅助局部给药 vismodegib 可减少人体基底细胞癌中刺猬基因的表达。
背景:全身给药的刺猬抑制剂(包括 vismodegib 和 sonidegib)被广泛用于治疗基底细胞癌(BCC)。临床前研究已经证实了消融点阵激光(AFL)辅助局部给药 vismodegib。这项探索性临床研究旨在评估AFL辅助局部给药vismodegib治疗BCC后瘤体内vismodegib的浓度以及对刺猬通路基因表达的影响:在一项开放标签临床试验中,16 例结节性 BCC(n = 9 例患者)接受了一次 CO2 -AFL(40 mJ/microbeam,10% 密度)治疗,随后局部使用 vismodegib 乳液。3-4 天后,对肿瘤活检样本(15 例)和血浆中的 vismodegib 浓度进行分析,并与接受口服治疗的患者样本(3 例)进行比较。通过聚合酶链式反应定量检测 GLI1、GLI2、PTCH1 和 PTCH2 的表达(7 例),并通过原位杂交检测 GLI1 的表达(3 例):AFL辅助局部用药后,在14/15个BCC中检测到了vismodegib,中位浓度为6.2 µmol/L,与口服vismodegib的患者BCC组织中的浓度(9.5 µmol/L,n = 3,p = 0.8588)相比,vismodegib的浓度更低。局部外用 vismodegib 可使瘤内 GLI1 表达减少 51%,GLI2 减少 55%,PTCH1 和 PTCH2 各减少 73%(p ≤ 0.0304),与 vismodegib 浓度无关(p ≥ 0.3164)。原位杂交表明,GLI1的表达仅限于肿瘤组织,并在vismodegib暴露后下调:结论:单次AFL辅助局部应用vismodegib可产生临床相关的瘤内药物浓度,并显著降低刺猬通路基因的表达。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
5.40
自引率
12.50%
发文量
119
审稿时长
1 months
期刊介绍: Lasers in Surgery and Medicine publishes the highest quality research and clinical manuscripts in areas relating to the use of lasers in medicine and biology. The journal publishes basic and clinical studies on the therapeutic and diagnostic use of lasers in all the surgical and medical specialties. Contributions regarding clinical trials, new therapeutic techniques or instrumentation, laser biophysics and bioengineering, photobiology and photochemistry, outcomes research, cost-effectiveness, and other aspects of biomedicine are welcome. Using a process of rigorous yet rapid review of submitted manuscripts, findings of high scientific and medical interest are published with a minimum delay.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信