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Surgical Debulking Modifies Notch Signaling and May Improve Vismodegib Effectiveness for Locally Advanced Basal Cell
Natella Maglakelidze1, Samantha L Gettle1, Amy L Longenecker1
1Department of Dermatology, Penn State College of Medicine, Hershey, Pennsylvania, USA.
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.
Insights
Surgical debulking before vismodegib treatment for locally advanced basal cell carcinoma (LaBCC) may alter tumor molecular pathways. This approach showed clinical responses in some patients, suggesting potential for improved outcomes in LaBCC treatment.
Area of Science:
- Oncology
- Dermatology
- Molecular Biology
Background:
- Vismodegib is effective for locally advanced basal cell carcinoma (LaBCC), but side effects limit its use.
- Surgical debulking prior to vismodegib has shown promise for prolonged remission in LaBCC.
- Understanding molecular changes post-debulking is crucial for optimizing LaBCC therapy.
Purpose of the Study:
- To assess clinical outcomes of LaBCC patients treated with debulking followed by vismodegib.
- To analyze molecular changes in LaBCC tissue after surgical debulking.
Main Methods:
- Four LaBCC patients underwent debulking surgery followed by vismodegib.
- Punch biopsies of residual tumor tissue were collected one week post-debulking.
- RT-qPCR, immunoblot, and immunostaining analyzed Notch and Wnt signaling pathways.
Main Results:
- Elevated expression of PTCH1, HEY2, LGR6, FZD2, LEF1, ALCAM, and RUNX1 genes was observed post-debulking.
- Notch signaling was confirmed to be elevated in follow-up biopsies.
- Three out of four patients showed a clinical response to the combined therapy.
Conclusions:
- Surgical manipulation of LaBCC correlates with molecular pathway alterations.
- This combination therapy may offer a viable treatment strategy for LaBCC.
- Further research is needed to elucidate the mechanisms of cellular reprogramming induced by surgery.
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