Journal of Clinical and Aesthetic Dermatology

APR 2017

An evidence-based, peer-reviewed journal for practicing clinicians in the field of dermatology

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48 JCAD journal of clinical and aesthetic dermatology April 2017 • Volume 10 • Number 4 C A S E R E P o R T pathway has the potential of providing a higher rate of tumor regression compared to a single blocker for the treatment of advanced BCC, while limiting or delaying the development of acquired Hh pathway resistance (Figure 2). Vismodegib is an oral Hh pathway inhibitor that works at a receptor site on smoothened (SMO), a critical Hh pathway component. It is United States Food and Drug Administration (FDA)-approved for the treatment of advanced and metastatic BCC. Similarly, itraconazole inhibits Hh pathway activation at the level of SMO, but at a receptor that is distinct from the receptor that binds vismodegib. 2 The Hh pathway blocking effect of itraconazole is dose-dependent and independent of its well- known antifungal activity. 2 Imiquimod, a topical imidazoquinoline, has antitumor properties via toll-like receptor agonist activity that leads to synthesis and release of various cytokines. 3 Additionally, imiquimod has been shown to repress Hh signalling activity via adenosine receptor activation (ADORA/PKA). This is far removed downstream from SMO and is separate from the inhibition sites of vismodegib and itraconazole. 3 Imiquimod is FDA- approved for the treatment of superficial BCC on the trunk and extremities, excluding sensitive areas such as the face. The off-label use of topical 5% imiquimod on the face for ulcerative BCC has been shown to promote healing with minimal scarring. 4 Mindful of the common side effects of erythema, crusting, and scabbing, the authors delayed imiquimod therapy to ensure adherence with vismodegib and itraconazole if the patient could not tolerate the skin irritation. The authors' patient received outstanding results with side effects comparable to vismodegib therapy alone. At four months, there was no clinical or histological evidence of the locally advanced BCC. This is much shorter than vismodegib monotherapy for locally advanced BCC, with a 7.6-month median duration of response and only 21 percent of complete recovery. 5,6 Compared to vismodegib, itraconazole is less effective in reducing Hh pathway expression. 7,8 Furthermore, its lack of response in vismodegib- resistant patients suggests that itraconazole may be more useful as an adjunct, as opposed to a second-line monotherapy. 7 Since the side effects of each blocker utilized by the authors' patient are different and not additive, their use in combination may provide for increased and prolonged efficacy with a similar side effect profile. This additive inhibitory effect on Hh-dependent Figures 1A–1C. Clinical photos of a patient with basal cell carcinoma receiving the triple hedgehog pathway inhibition therapy. (A) Basal cell carcinoma around the right lower eyelid and medial canthus pretreatment. (B) Crusting of the lower eyelid and right cheek after two weeks of daily topical imiquimod. (C) Complete resolution at four weeks of the combined hedgehog inhibition A B C

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