An evidence-based, peer-reviewed journal for practicing clinicians in the field of dermatology
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49 JCAD journal of clinical and aesthetic dermatology April 2017 • Volume 10 • Number 4 C A S E R E P o R T tumor growth, including tumors with acquired resistance to SMO inhibitors, has been reported using a combination of itraconazole and arsenic trioxide in mice. 9 While it is not possible to make generalizations from the treatment of a single patient, results seen with the authors' patient should encourage the treatment of more patients with combination therapy. Clinical trials or the treatment of a larger group of patients with combination Hh inhibition is recommended to investigate the efficacy, adverse events, and incidence of resistance. REFERENCES 1. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8(10):743–754. 2. Kim J, Tang JY, Gong R, et al. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer cell. 2010;17(4):388–399. 3. Gruber W, Frischauf AM, Aberger F. An old friend with new skills: Imiquimod as novel inhibitor of hedgehog signaling in basal cell carcinoma. Oncoscience. 2014;1(9):567. 4. Yang JQ, Chen XY, Engle MY, Wang JY. Multiple facial basal cell carcinomas in xeroderma pigmentosum treated with topical imiquimod 5% cream. Dermatol Ther. 2015;28(4):243–247. 5. Chang AL, Solomon JA, Hainsworth JD, et al. Expanded access study of patients with advanced basal cell carcinoma treated with the Hedgehog pathway inhibitor, vismodegib. J Am Acad Dermatol. 2014;70(1):60–69. 6. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171–2179. 7. Kim DJ, Kim J, Spaunhurst K, et al. Open-label, exploratory Phase II trial of oral itraconazole for the treatment of basal cell carcinoma. J Clin Oncol. 2014;32(8):745–751. 8. Tang JY, Mackay-Wiggan JM, Aszterbaum M, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med. 2012;366(23):2180– 2188. 9. Kim J, Aftab BT, Tang JY, et al. Itraconazole and arsenic trioxide inhibit hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer cell. 2013;23(1):23–34. Figure 2. Mechanism of action of various Hedgehog pathway inhibitors. Both vismodegib and itraconazole antagonize Smoothened (SMo), but through independent pathways. Imiquimod stimulates adenosine receptor (ADoRA), which activates the protein kinase A (PKA)-mediated phosphorylation (P) of the GLI transcription factors. This mechanism is autonomous from its action as a TLR7 and TLR8 agonist in the inflammatory pathway. Arsenic trioxide inhibits hedgehog signaling by directly inhibiting GLI transcriptional activity.