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- W2891024789 abstract "e17035 Background: Vulval squamous cell carcinoma (VSCC) is predominantly a disease of the elderly; with three-quarters of cases occurring in those aged over 60 years. Currently, chemotherapy is only used as an adjunct to surgery in advanced disease or for palliation. Unfortunately, the treatment response of VSCC to chemotherapies is variable, and toxicity remains a major problem, rendering it unsuitable for most patients. Dysregulation of the Hedgehog (HH) pathway has been described in many cancers, and HH inhibitors are being employed for the treatment of many cancers displaying aberrant pathway activation. To this end, we set out to evaluate 1) whether the HH pathway is dysregulated in VSCC and 2) the therapeutic utility of using HH inhibitors in the treatment of VSCC. Methods: Immunohistochemical staining of HH pathway components was performed on formalin-fixed paraffin-embedded sections of a well-characterized cohort of 201 patients with primary VSCC. Expression of HH pathway proteins was then correlated with clinico-pathological data, disease recurrence and survival. A panel of VSCC-derived cell lines was examined for HH pathway activity using an HH-GLI luciferase reporter assay. The effects of HH inhibitors on the growth and viability of VSCC cell lines, alone and in combination with cisplatin, was examined by BrdU label incorporation and XTT viability assays. Results: The HH signaling pathway was found to be over-expressed in approximately 80% of VSCC cases. Moreover, patients whose tumours displayed Sonic HH (SHH) ligand overexpression were more likely to develop a local recurrence within 3 years. Two HH inhibitors, Itraconazole and LDE225, not only inhibited the growth of VSCC cell lines in a dose-dependent manner, but also sensitized cells to the genotoxic affects of Cisplatin. Conclusions: We have shown for the first time that HH pathway is overexpressed in VSCC and that SHH overexpression may serve as a useful biomarker to predict local disease recurrence. In addition, results from our laboratory studies have shown that HH inhibitors may be used as a neo-adjuvant therapy to augment the actions of chemotherapeutic agents in this disease." @default.
- W2891024789 created "2018-09-27" @default.
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- W2891024789 date "2017-05-20" @default.
- W2891024789 modified "2023-09-22" @default.
- W2891024789 title "Sonic hedgehog inhibitors: Potential targeted therapy for squamous cell carcinoma of the vulva." @default.
- W2891024789 doi "https://doi.org/10.1200/jco.2017.35.15_suppl.e17035" @default.
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