Project description:Urolithin A is a gut microbiome derived postbiotic that has been shown to stimulate mitophagy, and improve muscle and mitochondrial health when administered orally to humans. In three separate randomized trials, we have now investigated the effect of topical administration of Urolithin A on skin aging features and on UVB-mediated photodamaged skin. Post-menopausal women with evidence of skin aging such as > Grade 3 wrinkle formation were included in a split-face/arm study design in the first trial (aging study 1; n=48), followed by a second larger trial (aging study 2; n=108) in middle-aged men and women focusing on wrinkle reduction. Healthy participants were included in the placebo-controlled, randomized UVB-induced trial (photo-damage trial; n=22). Participants were randomized to receive topical supplementation with either 0.5% Urolithin A cream or placebo for 8-weeks in a low-dose arm or 1% Urolithin A cream or placebo in the high-dose arm in theaging study 1. In theaging study 2participants were randomized to receive 1% UA in a day-cream, a night cream and a serum, that were compared to the untreated site. For thephoto-damage trial,topical patches containing either 0.5% or 1% UA or placebo cream were applied for 24-hours following UVB irradiation. The primary outcome in theaging study 1was an impact on biological pathways linked to skin aging in skin biopsies, and an impact on skin barrier function after 8-weeks. Key secondary endpoints were a change in facial wrinkle appearance (crow’s feet area). Theaging study 2focused on wrinkle reduction as a primary outcome. In the UVB-mediatedphoto-damage study, the primary read-out was the change in erythema after application. Molecular analyses were conducted on skin biopsies and usingex-vivosystems to investigate the mechanism of action mediating skin protective effects of Urolithin A. In theaging study 1, Urolithin A at 1% significantly up-regulated collagen synthesis pathways in human skin biopsies and led to a decrease in wrinkle depth on facial wrinkles. The lower dose had no significant impact. There was no change on skin barrier function with both doses suggesting maintenance of a healthy skin barrier function. Inaging study 2, topical application of Urolithin A at the 1% dose in different formulations (day-cream, night cream and serum) led to significant wrinkle reduction compared to the untreated side, confirming the previous findings. Skin hydration was improved significantly as well. In the third trial, investigating impact on photodamaged skin, Urolithin A application led to a significant decrease in UV-induced erythema (∼14%) compared to the untreated area, while placebo and lower dose UA cream’s showed no benefits. Urolithin A topical administration was safe and well-tolerated in all studies. UA also inhibited collagen degrading and pro-inflammatory pathways and up-regulated gene expression of biomarkers linked to induction of mitophagy and autophagy in human skin cells. Taken together, these clinical studies support the topical use of Urolithin A to manage and prolong skin health longevity by acting at the cellular level, supporting collagen structure, reducing wrinkle appearance and protecting against photoaging.

Project description:Background and rationale: EGFR represents the main and more studied signal activation pathway in the development of colorectal carcinoma. KRAS, NRAS, BRAF and PI3KA mutations and ERBB2 and MET amplification are responsible for most of the cases of primary resistance to anti-EGFR antibody treatments. Despite the identification of these resistance mechanisms, a primary resistance to the therapy was detected in a certain percentage of cases, in which tumour bio-molecular characteristics would suggest a possible response to anti-EGFR antibody treatment. In these cases, pathway activation mechanisms should exist, which act in an alternative, complementary or parallel way than the EGFR one, allowing tumour progression despite of EGFR pharmacological deactivation. Skin toxicity is a characteristic of drugs having EGFR as a target and it shows itself mainly as a sterile acneiform folliculitis together with neutrophils perifollicular infiltrates but also as skin xerosis and paronychia starting from the earliest cycles of treatment. This skin toxicity seems to be closely related to EGFR activation of pro-inflammatory cytokines able to activate specific inflammatory activators, which induce neutrophils granulocytes chemotaxis. Lycopene is a compound belonging to carotenoid group, largely contained in tomatoes and their derivatives, which has an extreme antioxidant activity. In Dermatology, prolonged use of β-carotenoids in general and of lycopene in particular in the diet showed to be effective in skin protection from ageing, sunlight and radiotherapy damages because these compounds may accumulate in skin and thus contribute to reduce free radicals and inflammation effects. Moreover, lycopene ability to induce apoptosis and to inhibit cell cycle progression in some types of tumour cells, both in vitro and in vivo, has already been described. Lycopene seems to be able to suppress significantly PCNA (Proliferating cell nuclear antigen, cofactor of DNA polymerase-β) and β-catenin nuclear expression in neoplastic cells, essential substrate of WNT/β-catenin pathway, which is itself closely connected to activating pathways often involved in carcinogenesis of some kinds of tumours, in particular of colorectal carcinoma, like Akt/GSK3β/β-catenin and Hippo pathways. For its proved skin anti-inflammatory activity as powerful free radicals scavenger, lycopene, which accumulates itself specifically in skin, could be effective in reducing anti-EGFR drugs toxicity. Contemporary use of lycopene could have a positive effect on anti-EGFR drugs treatment effectiveness in patients with metastatic colorectal carcinoma due to its ability to interfere with pathways involved in neoplastic cells proliferation. Estimated population:100 patients (50 for each of the two groups of treatment) Study Framework: In this study, patients suffering from metastatic colorectal cancer and submitted to therapy with panitumumab would be enrolled. According to indications, panitumumab would be used: in first line combined with Folfox or Folfiri; in second line combined with Folfiri or treatments containing Irinotecan in monotherapy in any therapeutic line in patients resistant to Fluoropyrimidines, Oxaliplatin and Irinotecan or intolerant to these drugs. Standard schedules of these treatments would be used. This is a phase-II, randomized, double-blind study between experimental prophylactic treatment with Lycopene vs placebo: * Treatment A - lycopene tablets 20 mg * Treatment B - placebo tablets Patients should take orally Lycopene/placebo after dinner (to promote its absorption), starting the day before the beginning of treatment with panitumumab for the entire duration of the therapy, until progression of the disease or definitive drug suspension for toxicity. Objectives of the study Primary objective: to assess the effectiveness of lycopene versus placebo in reducing skin toxicity induced by panitumumab in patients treated for metastatic colorectal carcinoma. Secondary objective: to assess lycopene pharmacokinetics Exploratory objectives: to assess lycopene effectiveness versus placebo in increasing panitumumab effectiveness in terms of Disease Control (DC), Objective Response (OR) and Stabilisation of the Disease (SD). To assess lycopene effectiveness versus placebo in increasing panitumumab effectiveness in terms of Progression Free Survival (PFS). As far as randomization is concerned, the two groups will be balanced according to sex, therapeutic line and institution in which patients will be treated.

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Pilot study of ceramide cream for the skin toxicity of cetuximab in advanced colorectal cancer.

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