Randomized controlled trial of fractionated laser resurfacing on aged skin as prophylaxis against actinic neoplasia

Abstract

BackgroundThe loss of insulin-like growth factor-1 (IGF-1) expression in senescent dermal fibroblasts during aging is associated with an increased risk of non-melanoma skin cancer (NMSC). We tested how IGF-1 signaling can influence photocarcinogenesis during chronic UVB exposure to determine if fractionated laser resurfacing (FLR) of aged skin which upregulates dermal IGF-1 levels can prevent the occurrence of actinic keratosis (AK) and NMSC. MethodsA human skin/immunodeficient mouse xenografting model was used to test the effects of a small molecule inhibitor of the IGF-1 receptor on chronic UVB radiation.Subsequently, the durability of FLR treatment was tested on a cohort of human subjects aged >65. Finally, 48 subjects aged 60 and older with considerable actinic damage were enrolled in a prospective randomized clinical trial in which they underwent a single unilateral FLR treatment of one lower arm. Numbers of AKs/NMSCs were recorded on both extremities for up to 36 months in blinded fashion. Results:Xenografting studies revealed chronic UVB treatment with a topical IGF-1R inhibitor resulted in a pro-carcinogenic response. A single FLR treatment was durable in restoring appropriate UVB response in geriatric skin for at least two years. FLR resulted in sustained reduction in numbers of AKs and decreased numbers of NMSC in the treated (24) versus untreated (2) arms. 3 Interpretation:The elimination of senescent fibroblasts via FLR reduced the pro-carcinogenic UVB response of aged skin. Thus, wounding therapies are potentially effective prophylaxis for managing high-risk populations.Trial Registration: ClinicalTrials.gov NCT03906253.

Wounding Therapies for Prevention of Photocarcinogenesis

“…Consistent with this notion, recent studies by our group xenografted human skin onto immunodeficient mice, and the human skin grafts underwent a chronic UVB carcinogenesis protocol with/without treatment with a topical IGF-1R inhibitor. A 20 week UVB treatment of the skin treated with IGF-1R inhibitor, which would mimic geriatric skin, resulted in formation of actinic neoplastic (AKs/early SCC) lesions, findings not seen in vehicle irradiated skin (20). The data from these studies suggests that defective IGF-1/IGF-1R signaling due to senescent dermal fibroblasts is an important cause of geriatric NMSC.…”

“…Patients underwent a single treatment of FLR on the upper extremity of aged skin. They were examined at three month postwounding and every six months thereafter for a current 36month follow-up period (20). To determine the effectiveness of FLR in reducing the occurrence of AKs, the ratio of the number of AKs on FLR-treated arms to untreated arms was tracked.…”

“…However, if IGF-1R is inactive due to diminished IGF-1, keratinocytes may continue to propagate its procarcinogenic DNA damage to its daughter cells (11,12,19). This increases the likelihood for development of NMSC (20).…”

“…In recent years, novel treatments aimed for geriatric patients both predisposed and exposed to NMSC have been developed. One such modality is wounding therapy, which attempts to reverse the geriatric fibroblast senescence phenotype by inducing a "wounding response" (19)(20)(21)(22)(23). This effectively serves to rejuvenate geriatric skin to a more youthful phenotypic and constitutive expression.…”

Creatine and Nicotinamide Prevent Oxidant-Induced Senescence in Human Fibroblasts

“…In as much as the increased numbers of senescent fibroblasts found in aged skin result in a significant IGF-1 deficiency, strategies to prevent/and or treat this could have clinical use. In particular, our group recently reported that wounding of geriatric skin with fractionated laser resurfacing which upregulates active fibroblasts could prevent actinic neoplasia including NMSC [48]. Moreover, enzymatic treatment of photoaged skin with agents such as elastase could have beneficial effects [49].…”