Exploring the use of ingenol mebutate to prevent non-melanoma skin cancer

Abstract

Non-melanoma skin cancer is the most frequently occurring cancer in Caucasians today. Incidence rates in Europe have increased steadily since the 1960s and more than tripled over the last 50 years. Despite primary preventative efforts, incidences of non-melanoma skin cancer continue to rise and development of effective chemopreventative strategies is needed. In 2013, ingenol mebutate was approved in Denmark as a new topical drug for field-directed treatment for actinic keratoses. Ingenol mebutate has a dual mechanism of action, causing initial cell death, followed by an immune activation. The treatment induces an acute inflammation, manifesting as local skin responses, often accompanied by pain and pruritus. The severity of local skin responses for a given patient is unpredictable, and some individuals may develop insufferable inflammation. The overall aim of the thesis was to investigate if ingenol mebutate could be used as a chemopreventive agent to prevent development of non-melanoma skin cancer with minimal side effects. Specific aims included: Determine if ingenol mebutate can prevent progression of histological photodamage and squamous cell carcinoma (murine). Determine if ingenol mebutate can reverse clinical actinic damage in patients with multiple actinic keratoses and fieldcancerized skin (clinical). Determine if a topical glucocorticoid (clobetasol propionate) can reduce ingenol mebutate-induced local skin responses, pain, and pruritus without compromising the treatment efficacy (murine clinical). In two in vivo murine studies, ingenol mebutate's effect on photodamage and squamous cell carcinoma formation was investigated. Mice were irradiated with solar simulated ultraviolet radiation. During the first 20 weeks, 5 single applications with ingenol mebutate were given at four-week intervals with and without concurrent application of clobetasol propionate. Prophylactic treatments with ingenol mebutate prevented progression of histological photodamage of all investigated characteristics, including keratosis grade, epidermal hypertrophy, dysplasia, and dermal actinic damage. In addition, tumor formation was postponed by 3 weeks. In the clinical trial, patients with multiple actinic keratoses and field-cancerized skin were treated with ingenol mebutate, according to label, with and without sequential application of clobetasol propionate. Ingenol mebutate treatments were found to clear overall 86% of all actinic keratoses, exerting a therapeutic effect on all severity grades; cure rates were 88%, 70%, and 60% for Grade I, II, and III actinic keratoses, respectively. Ingenol mebutate treatments generated erythema, flaking, crusting, vesiculation, swelling/bleeding, and ulceration. Concurrent application of clobetasol propionate increased local skin responses in murine skin, likely due to an enhanced penetration of ingenol mebutate that resulted in a greater therapeutic effect compared to ingenol mebutate alone. In patients with actinic keratoses, sequential application of ingenol mebutate and clobetasol propionate did not reduce local skin responses, pain, or pruritus, nor did it affect treatment efficacy compared to ingenol mebutate alone. In conclusion, the thesis highlights ingenol mebutate's potential as a prophylactic remedy for non-melanoma skin cancer with promise to support primary preventative efforts in reducing non-melanoma skin cancer incidence.