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":"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。","authors":"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","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":"{\"title\":\"Laser-assisted topical delivery of vismodegib reduces hedgehog gene expression in human basal cell carcinomas in vivo\",\"authors\":\"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\",\"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}","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}
Laser-assisted topical delivery of vismodegib reduces hedgehog gene expression in human basal cell carcinomas in vivo
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.
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.