PDF(Pubmed)
Abstract：
Smoothened inhibitors, such as vismodegib, exhibit remarkable success in treating patients with locally advanced basal cell carcinoma (LaBCC). Yet, vismodegib efficacy is hindered by notable side effects, which often lead to treatment discontinuation and subsequent relapse in patients with LaBCC. Prolonged remission was previously reported in patients with LaBCCs who underwent surgical debulking before starting vismodegib. In this study, we enrolled 4 patients with LaBCC who underwent debulking followed by vismodegib therapy to assess their clinical outcomes and analyze the cutaneous molecular changes occurring as a result of surgical intervention. After LaBCC debulking, patients underwent a punch biopsy of residual basal cell carcinoma tissue 1 week later. RT-qPCR analysis of 24 Notch and Wnt signaling-associated genes revealed elevated PTCH1, HEY2, LGR6, FZD2, LEF1, ALCAM, and RUNX1 expressions in follow-up biopsies compared with those in patient-matched debulked tissue. Immunoblot and immunostaining further confirmed elevated Notch signaling in follow-up biopsy tissue compared with that in patient-matched debulked tumor tissue. Patients 1, 3, and 4 displayed a clinical response to debulking followed by vismodegib, whereas patient 2 was lost to follow-up after debulking. These findings suggest that surgical manipulation of LaBCCs is correlated with molecular alterations in signaling pathways associated with cellular reprogramming.
摘要：
平滑抑制剂，比如vismodegib,在治疗局部晚期基底细胞癌（LaBCC）患者方面取得了显着成功。然而，Vismodegib的疗效受到明显副作用的阻碍，这通常会导致LaBCC患者停止治疗并随后复发。以前曾报道过LaBCC患者在开始vismodegib之前接受了手术切除手术的长期缓解。在这项研究中,我们纳入了4例LaBCC患者,这些患者接受了减瘤后再接受vismodegib治疗,以评估其临床结局,并分析手术干预后皮肤分子的变化.LaBCC剔除后，1周后,患者对残留的基底细胞癌组织进行穿刺活检.对24个Notch和Wnt信号相关基因的RT-qPCR分析显示PTCH1，HEY2，LGR6，FZD2，LEF1，ALCAM，随访活检中的RUNX1表达与患者匹配的切除组织中的表达相比。免疫印迹和免疫染色进一步证实，与患者匹配的切除肿瘤组织相比，后续活检组织中的Notch信号传导升高。患者1、3和4对减积后的vismodegib表现出临床反应，而患者2在减积后失去随访。这些发现表明，LaBCC的手术操作与细胞重编程相关的信号通路中的分子改变有关。
