Abstract
The rapid and strong clinical efficacy of the first-in-class, ingenol mebutate, against actinic keratosis (AK) has resulted in its recent approval. We conducted the first comprehensive analysis of the cellular and molecular mode of action of topical ingenol mebutate 0.05% gel in both AK and uninvolved skin of 26 patients in a phase I, single-center, open-label, within-patient comparison. As early as 1 day after application, ingenol mebutate induced profound epidermal cell death, along with a strong infiltrate of CD4+ and CD8+ T-cells, neutrophils, and macrophages. Endothelial ICAM-1 activation became evident after 2 days. The reaction pattern was significantly more pronounced in AK compared with uninvolved skin, suggesting a tumor-preferential mode of action. Extensive molecular analyses and transcriptomic profiling of mRNAs and microRNAs demonstrated alterations in gene clusters functionally associated with epidermal development, inflammation, innate immunity, and response to wounding. Ingenol mebutate reveals a unique mode of action linking directly to anti-tumoral effects.Trial Registration: ClinicalTrials.gov NCT01387711
Highlights
Actinic keratosis (AK) is common in fair-skinned people
local skin response (LSR) were dominated by erythema and, to a lesser extent, flaking/scaling, swelling, and vesiculation/pustulation
When exact numbers of cells affected by ingenol mebutate were compared, a clear and statistically highly significant preference of actinic keratosis (AK) lesions regarding numerous quantitative parameters was established
Summary
Actinic keratosis (AK) is common in fair-skinned people. In Europe, prevalence ranges from 11% to 25% in people aged !40 years [1,2,3,4]. AK lesions are early pre-malignant epithelial skin tumors induced by chronic exposure to UV irradiation and are characterized histologically by dysregulated keratinocyte proliferation and abnormal epithelial architecture [5, 6]. Substantial evidence suggests the presence of non-clinically visible AK adjacent to clinical lesions [7]. Activation of oncogenic signaling pathways, and gene.
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