Effects of Topical Diclofenac on Tumor Metabolism

Study Overview
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Brief Summary
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The rationale of this study is to investigate the effects of topical diclofenac on tumor metabolism in the treatment of actinic keratoses in immunocompetent and immunocompromised patients. Study hypothesis is that topical diclofenac lowers lactate level in skin biopsies of actinic keratoses. Planned number of patients is 38. This study is a monocenter study investigating the effects of 3% diclofenac in 2.5% hyaluronic acid gel on tumor metabolism in the treatment of actinic keratoses. Treatment duration is 3 months. Skin biopsies will be obtained before treatment, at the end of the treatment and four weeks after the treatment. Control biopsies at visit 1 and 3 are performed in healthy, sun damaged and untreated skin. Evaluation of efficacy will be performed at the end of the treatment and four weeks after the treatment. Duration of treatment is 3 months (±4 weeks). Approximately 0,5g Solaraze® 3% gel is applied on a 5cm x 5cm lesion. Solaraze® 3% gel is applied twice daily on the study lesions.

Detailed Description
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Neoplastic cells show an increased glucose metabolism and glycolysis which is associated with high lactate concentrations. There is also data for several tumor entities that high levels of lactate in the tumor are associated with tumor progression, metastasis and poor clinical outcome. Kreutz et al. demonstrated that diclofenac inhibits tumor cell proliferation in vitro and tumor growth in vivo via COX-independent effects on glucose metabolism. Diclofenac is taken up by tumor cells and inhibits tumor cell proliferation through inhibition of the oncogene MYC and subsequently glycolysis and block of lactate transport. MYC regulates genes involved in glycolysis and is upregulated in neoplastic cells, which is in line with the metabolic switch to glycolysis, the so called Warburg effect, that cancer cells show. Although these results were found in vitro using human melanoma cells and in vivo in a mouse model, a similar mechanism of action is assumed to be relevant for the treatment of actinic keratoses with topical diclofenac. However tumor metabolism in diclofenac-treated actinic keratoses has never been investigated. To investigate the mechanism of action of diclofenac in the treatment of actinic keratoses, a clinical study analyzing particularly lactate levels, glycolysis and inflammatory infiltrate is needed.

Official Title
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Prospective, Controlled and Monocentric Study to Evaluate the Effects of Topical 3% Diclofenac in 2.5% Hyaluronic Acid Gel on Tumor Metabolism in the Treatment of Actinic Keratoses in Immunocompetent and Immunocompromised Patients

Conditions
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Actinic Keratoses

Intervention / Treatment
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* Drug: 3% diclofenac in 2.5% hyaluronic acid gel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent has been signed prior to or at Screening Visit Caucasian male and female patients Age > 18 years Negative pregnancy test in women of childbearing age Clinical diagnosis of actinic keratosis (AK) A minimum of three AK lesions Exclusion Criteria in immunocompromised patients : Concomitant UV-phototherapy Pregnancy or lactation Women in child-bearing age who do not use highly efficient contraceptive methods (<1% failure rate per year) Skin diseases that might interfere with response evaluation of study treatment Topical pretreatment of the AK study lesions with photodynamic therapy, Solaraze® 3% gel, Aldara®, 5-FU, or polyphenon E during the 8 weeks preceding study treatment Radiation therapy performed in the treatment area during the 3 months preceding study therapy Systemic treatment with diclofenac Known intolerance to diclofenac or to any other ingredient of Solaraze® 3% gel Conditions that might interfere with the ability to understand the study and thus give written informed consent Simultaneous participation in another clinical study or participation in another clinical study in the 30 days directly preceding inclusion Suspected lack of compliance Exclusion criteria in immunocompetent patients: Concomitant UV-phototherapy Pregnancy or lactation Women in child-bearing age who do not use highly efficient contraceptive methods (<1% failure rate per year) Patients with clinically relevant suppression of the immune system (e.g. drug induced, infection) Skin diseases that might interfere with response evaluation of study treatment Topical pretreatment of the AK study lesions with photodynamic therapy, Aldara®, Solaraze® 3% gel , 5-FU, or polyphenon E during the 8 weeks preceding study treatment Systemic treatment with cytostatic drugs or radiation therapy performed in the treatment area during the 3 months preceding study therapy Systemic treatment with diclofenac Known intolerance to diclofenac or to any other ingredient of Solaraze® 3% gel Conditions that might interfere with the ability to understand the study and thus give written informed consent Simultaneous participation in another clinical study or participation in another clinical study in participation in another clinical study in the 30 days directly preceding inclusion Suspected lack of compliance

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Diclofenac<br>3 % diclofenac in 2.5% hyaluronic acid gel (Solaraze® 3% gel) is applied twice daily in the treatment area. 3 % diclofenac in 2.5% hyaluronic acid gel (Solaraze® 3% gel) is to be applied 1cm beyond the single AK. | Drug: 3% diclofenac in 2.5% hyaluronic acid gel<br> <br> * Other names: Solaraze Gel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lactate level in skin biopsies of actinic keratoses | Assessment of the effects of topical 3% diclofenac in 2.5% hyaluronic acid gel on lactate level in skin biopsies of actinic keratoses. Skin biopsies of actinic keratoses are obtained prior to treatment and 4 weeks after the treatment. | 4 weeks after the treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lactate level in skin biopsies of healthy skin in a subpopulation | Assessment of the effects of topical 3% diclofenac in 2.5% hyaluronic acid gel on lactate level in skin biopsies of actinic keratoses compared to untreated sun damaged, healthy skin in a subpopulation | Before treatment and 4 weeks after the treatment | 
| Glycolysis-relevant proteins evaluated using PCR and Westernblot techniques | Glycolysis-relevant proteins evaluated using PCR and Westernblot techniques | at the end of the treatment and 4 weeks after the treatment | 
| Metabolic changes (e.g. glucose, amino acids) | Metabolic changes (e.g. glucose, amino acids) evaluated by NMR methods and bioluminescence imaging techniques | at the end of the tretment and 4 weeks after the treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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actinic keratoses, tumor metabolism, glycolysis, diclofenac, warburg effect