Investigational drugs currently in phase II clinical trials for actinic keratosis

References

• Goldberg L, Mamelak A. Review of actinic keratosis. Part 1: etiology, epidemiology and clinical presentation. J Drug Dermatol. 2010;9:1125–1132.
   PubMed Web of Science ®Google Scholar
• Campione E, Ventura A, Diluvio L, et al. Current developments in pharmacotherapy for actinic keratosis. Expert Opin Pharmacother. 2018;19:1693–1704.
   PubMed Web of Science ®Google Scholar
• Lallas A, Pyne J, Kyrgis A, et al. The clinical and dermoscopic features of invasive cutaneous squamous cell carcinoma depend on the histopathological grade of differentiation. Br J Dermatol. 2015;172:1308–1315.
   PubMed Web of Science ®Google Scholar
• Boukamp P. Non-melanoma skin cancer: what drives tumor development and progression? Carcinogenesis. 2005;26:1657–1667.
   PubMed Web of Science ®Google Scholar
• Kathpalia V, Mussak E, Chow S, et al. Genome-wide transcriptional profiling in human squamous cell carcinoma of the skin identifies unique tumor-associated signatures. J Dermatol. 2006;33:309–318.
   PubMed Web of Science ®Google Scholar
• Campione E, Paternò E, Candi E, et al. The relevance of piroxicam for the prevention and treatment of nonmelanoma skin cancer and its precursors. Drug Des Devel Ther. 2015;9:5843–5850.
   PubMed Web of Science ®Google Scholar
• Tessari G, Girolomoni G. Nonmelanoma skin cancer in solid organ transplant recipients: update on epidemiology, risk factors, and management. Dermatol Surg. 2012;38:1622–1630.
   PubMed Web of Science ®Google Scholar
• Garofalo V, Ventura A, Mazzilli S, et al. Treatment of multiple actinic keratosis and field of cancerization with topical piroxicam 0.8% and sunscreen 50+ in organ transplant recipients: a series of 10 cases. Case Rep Dermatol. 2017;9:211–216.
   PubMed Web of Science ®Google Scholar
• Campione E, Di Prete M, Diluvio L, et al. Efficacy of ingenol mebutate gel for actinic keratosis in patients treated by thiazide diuretics. Clin Cosmet Investig Dermatol. 2016;9:405–409.
   PubMed Web of Science ®Google Scholar
• Amspang S, Pottergard A, Friis S, et al. Statin use and risk of nonmelanoma skin cancer: a nationwide study in Denmark. Br J Cancer. 2015;112:153–156.
   PubMed Web of Science ®Google Scholar
• Mazzilli S, Garofalo V, Ventura A, et al. Effects of topical 0.8% piroxicam and 50+ sunscreen filters on actinic keratosis in hypertensive patients treated with or without photosensitizing diuretic drugs: an observational cohort study. Clin Cosmet Investig Dermatol. 2018;11:485–490.
   PubMed Web of Science ®Google Scholar
• Iannacone M, Gheit T, Giuliano A, et al. Case-control study of genus-beta human papillomaviruses in plucked eyebrow hairs and cutaneous squamous cell carcinoma. Int J Cancer. 2014;34:2231–2244.
   Google Scholar
• Harwood C, Proby C. Human papillomaviruses and non-melanoma skin cancer. Curr Opin Infect Dis. 2002;15:101–114.
   PubMed Web of Science ®Google Scholar
• Hussein M, Ahmed R. Analysis of the mononuclear inflammatory cell infiltrate in the non-tumorigenic, pre-tumorigenic and tumorigenic keratinocytic hyperproliferative lesions of the skin. Cancer Biol Ther. 2005;4:819–821.
   PubMed Web of Science ®Google Scholar
• Rower-Huber J, Patel M, Forschner T, et al. Actinic keratosis is an early in situ squamous cell carcinoma: a proposal for reclassification. Br J Dermatol. 2007;156:8–12.
   PubMed Web of Science ®Google Scholar
• Jetter N, Chandan N, Wang S, et al. Field Cancerization therapies for management of actinic keratosis: a narrative review. Am J Clin Dermatol. 2018;19:543–557.
   PubMed Web of Science ®Google Scholar
• Puviani M, Galloni C, Marchetti S, et al. Efficacy of a film-forming medical device containing sunscreen (50+) and piroxicam 0.8% in actinic keratosis and field cancerization: a multicenter, assessor-blinded, 3 month trial. Curr Med Res Opin. 2017;33:1255–1259.
   PubMed Web of Science ®Google Scholar
• Diluvio L, Bavetta M, Costanza G, et al. Monitoring treatment response in patients affected by actinic keratosis: dermoscopic assessment and metalloproteinases evaluation after piroxicam 0.8% and sunfilter cream. Dermatol Ther. 2018;14:e12772.
   Google Scholar
• Babino G, Diluvio L, Bianchi L, et al. Long-term use of a new topical formulation containing piroxicam 0.8% and sunscreen: efficacy and tolerability on actinic keratosis. A proof of concept study. Curr Med Res Opin. 2016;32:1345–1349.
   PubMed Web of Science ®Google Scholar
• ClinicalTrials.Gov. U.S. National Library of Medicine [Internet]. [Cited 2018 Dec 18]. Available from: www.ClinicalTrials.Gov.
   Google Scholar
• Cancer.gov. The National Cancer Institute-NCI [Internet]. [Cited 2018 Dec 20]. Available from: www.cancer.gov.
   Google Scholar
• PubChem-open chemistry database. U.S. National Library of Medicine [Internet]. [Cited 2018 Dec 21]. Available from: www.pubchem.ncbi.nlm.nih.gov.
   Google Scholar
• Wan M, Lin J. Current evidence and applications of photodynamic therapy in dermatology. Clin Cosmet Investig Dermatol. 2014;7:145–163.
   PubMedGoogle Scholar
• Cohen D, Lee P. Photodynamic therapy for non-melanoma skin cancers. Cancers (Basel). 2016;8:90.
   PubMed Web of Science ®Google Scholar
• Lang K, Lehmann P, Bolsen K, et al. Aminolevulinic acid: pharmacological profile and clinical indication. Expert Opin Investig Drugs. 2001;10:1139–1156.
   PubMed Web of Science ®Google Scholar
• Reinhold U. A review of BF-200 ALA for the photodynamic treatment of mild-to-moderate actinic keratosis. Future Oncol. 2017;13:2413–2428.
   PubMed Web of Science ®Google Scholar
• BF200 [Internet]. NCI DRUG Dict. [Cited 2018 Dec 21]. Available from: https://www.cancer.gov/publications/dictionaries/cancer-drug.
   Google Scholar
• Vegter S, Tolley K. A network meta-analysis of the relative efficacy of treatments for actinic keratosis of the face or scalp in Europe. PLoS One. 2014;9:e96829.
   PubMed Web of Science ®Google Scholar
• Helander L, Sharma A, Krokan H, et al. Photodynamic treatment with hexyl-aminolevulinate mediates reversible thiol oxidation in core oxidative stress signaling proteins. Mol Biosyst. 2016;12:796–805.
   PubMedGoogle Scholar
• Neittaanmaki-Perttu N, Gronroos M, Karppinen T, et al. Hexyl-5-aminolaevulinate 0·2% vs. methyl-5-aminolaevulinate 16% daylight photodynamic therapy for treatment of actinic keratoses: results of a randomized double-blinded pilot trial. Br J Dermatol. 2016;174:427–429.
   PubMed Web of Science ®Google Scholar
• Schön MP, Schön M. The small-molecule immune response modifier imiquimod–its mode of action and clinical use in the treatment of skin cancer. Expert Opin Ther Targets. 2006;10:69–76.
   PubMed Web of Science ®Google Scholar
• Bianchi L, Campione E, Marulli G, et al. Actinic keratosis treated with an immune response modifier: a case report of six patients. Clin Exp Dermatol. 2003;28:39–41.
   PubMed Web of Science ®Google Scholar
• Gebauer K, Shumack S, Cowen PS. Effect of dosing frequency on the safety and efficacy of imiquimod 5% cream for treatment of actinic keratosis on the forearms and hands: a phase II, randomized placebo-controlled trial. Br J Dermatol. 2009;16:897–903.
   Google Scholar
• Engel AL, Holt GE, Lu H. The pharmacokinetics of Toll-like receptor agonists and the impact on the immune system. Expert Rev Clin Pharmacol. 2011;4:275–289.
   PubMedGoogle Scholar
• Hampson P, Chahal H, Khanim F, et al. PEP005, a selective small-molecule activator of protein kinase C, has potent antileukemic activity mediated via the delta isoform of PKC. Blood. 2005;106:1362–1368.
   Google Scholar
• Hampson P, Wang K, Milverton L, et al. Kinetics of ERK1/2 activation determine sensitivity of acute myeloid leukaemia cells to the induction of apoptosis by the novel small molecule ingenol 3-angelate (PEP005). Apoptosis. 2010;15:946–955.
   PubMed Web of Science ®Google Scholar
• Stockfleth E, Bastian M. Pharmacokinetic and pharmacodynamic evaluation of ingenol mebutate for the treatment of actinic keratosis. Expert Opin Drug Metab Toxicol. 2018;15:911–918.
   Web of Science ®Google Scholar
• Parker C, Kuttruff C, Galmozzi A, et al. chemical proteomics identifies SLC25A20 as a functional target of the ingenol class of actinic keratosis drugs. ACS Cent Sci 2017;3:1276–1285.
   Google Scholar
• Anderson L, Jarratt M, Schmieder G, et al. Tolerability and pharmacokinetics of ingenol mebutate 0.05% gel applied to treatment areas up to 100cm(2) on the forearm(s) of patients with actinic keratosis. J Clin Aesthet Dermatol. 2014;7:19–29.
   PubMedGoogle Scholar
• Herranz P, Morton C, Dirschka T, et al. Low-dose 0.5% 5-Fluorouracil/10% salicylic acid topical solution in the treatment of actinic keratoses. J Cutan Med Surg. 2016;20:555–561.
   PubMed Web of Science ®Google Scholar
• Simon J, Dominicus R, Karl L, et al. A prospective randomized exploratory study comparing the efficacy of once-daily topical 0.5% 5-fluorouracil in combination with 10.0% salicylic acid (5-FU/SA) vs. cryosurgery for the treatment of hyperkeratotic actinic keratosis. J Eur Acad Dermatol Venereol. 2015;29:881–889.
   PubMed Web of Science ®Google Scholar
• Buckman S, Gresham A, Hale P, et al. COX-2 expression is induced by UVB exposure in human skin: implications for the development of skin cancer. Carcinogenesis. 1998;19:723–729.
   PubMed Web of Science ®Google Scholar
• Higashi Y, Kanekura T, Kanzaki T. Enhanced expression of cyclooxygenase (COX)-2 in human skin epidermal cancer cells: evidence for growth suppression by inhibiting COX-2 expression. Int J Cancer. 2000;86:667–671.
   PubMed Web of Science ®Google Scholar
• Rundhaug J, Mikulec C, Pavone A, et al. A role for cyclooxygenase-2 in ultraviolet light-induced skin carcinogenesis. Mol Carcinog. 2007;46:692–698.
   PubMed Web of Science ®Google Scholar
• Liebman T, Stein J, Polsky D. Cyclo-oxygenase-2 inhibitors for chemoprevention of nonmelanoma skin cancer: is there a role for these agents? J Am Acad Dermatol. 2013;68:173–176.
   PubMed Web of Science ®Google Scholar
• Elmets C, Viner J, Pentland A, et al. Chemoprevention of nonmelanoma skin cancer with celecoxib: a randomized, double-blind, placebo-controlled trial. J Natl Cancer Inst. 2010;102:1835–1844.
   PubMed Web of Science ®Google Scholar
• Brickman C, Behar V, Becker O. VDA-1102, a first-in-class VDAC/HK modulator entering phase 1/2 drug development, for treatment of actinic keratosis and cutaneous squamous cell carcinoma. JAAD. 2016;74:AB207.
   Web of Science ®Google Scholar
• Wu C, Liang C, Shiu L, et al. Solanum incanum extract (SR-T100) induces human cutaneous squamous cell carcinoma apoptosis through modulating tumor necrosis factor receptor signaling pathway. Dermatol Sci. 2011;63:83–92.
   PubMed Web of Science ®Google Scholar
• Krol S, Kielbus M, Rivero-Muller A. Comprehensive review on betulin as a potent anticancer agent. Biomed Res. 2015;2015:584189.
   PubMed Web of Science ®Google Scholar
• Huyke C, Laszczyk M, Sceffler A, et al. Treatment of actinic keratoses with a novel betulin-based oleogel. A prospective, randomized, comparative pilot study. J Dtsch Dermatol Ges. 2009;7:128–133.
   PubMed Web of Science ®Google Scholar
• Huyke C, Laszczyk M, Scheffler A, et al. Treatment of actinic keratoses with birch bark extract: a pilot study. J Dtsch Dermatol Ges. 2006;4:132–136.
   PubMedGoogle Scholar
• Pflugfelder A, Andonov E, Weide B, et al. Lack of activity of betulin-based Oleogel-S10 in the treatment of actinic keratoses: a randomized, multicentre, placebo-controlled double-blind phase II trial. Br J Dermatol. 2015;172:926–932.
   PubMed Web of Science ®Google Scholar
• van der Kolk T, Dillingh M, Rijneveld R, et al. Topical ionic contra-viral therapy comprised of digoxin and furosemide as a potential novel treatment approach for common warts. J Eur Acad Dermatol Venereol. 2017;31:2088–2090.
   PubMed Web of Science ®Google Scholar
• Passeri D, Doldo E, Tarquini C, et al. Loss of CRABP-II characterizes human skin poorly differentiated squamous cell carcinomas and favors DMBA/TPA-induced carcinogenesis. J Invest Dermatol. 2016;135:1255–1266.
   Google Scholar
• Pegg A. Polyamine metabolism and its importance in neoplastic growth and a target for chemotherapy. Cancer Res. 1988;48:759–774.
   PubMed Web of Science ®Google Scholar
• Takigawa M, Verma A, Simsiman R, et al. Inhibition of mouse skin tumor promotion and of promoter-stimulated epidermal polyamine biosynthesis by alpha-difluoromethylornithine. Cancer Res. 1983;43:3732–3738.
   PubMed Web of Science ®Google Scholar
• Verma A, Duvick L, Ali M. Modulation of mouse skin tumor promotion by dietary 13-cis-retinoic acid and alpha-difluoromethylornithine. Carcinogenesis. 1986;7:1019–1023.
   PubMed Web of Science ®Google Scholar
• Weeks C, Herrmann A, Nelson F, et al. alpha-Difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, inhibits tumor promoter-induced polyamine accumulation and carcinogenesis in mouse skin. Proc Natl Acad Sci U S A. 1982;79:6028–6032.
   PubMed Web of Science ®Google Scholar
• Alberts D, Dorr R, Einspahr J, et al. Chemoprevention of human actinic keratoses by topical 2-(difluoromethyl)-dl-ornithine. Cancer Epidemiol Biomarkers Prev. 2000;9:1281–1286.
   PubMed Web of Science ®Google Scholar
• Bartels P, Yozwiak M, Einspahr J, et al. Chemopreventive efficacy of topical difluoromethylornithine and/or triamcinolone in the treatment of actinic keratoses analyzed by karyometry. Anal Quant Cytol Histol. 2009;31:355–366.
   PubMedGoogle Scholar
• Jeter J, Curiel-Lewandrowski C, Stratton S, et al. Phase IIB randomized study of topical difluoromethylornithine and topical diclofenac on sun-damaged skin of the forearm. Cancer Prev Res (Phila). 2016;9:128–134.
   PubMed Web of Science ®Google Scholar
• Chen T, Fonseca C, Schönthal A. Preclinical development and clinical use of perillyl alcohol for chemoprevention and cancer therapy. Am J Cancer Res. 2015;5:1580–1593.
   PubMed Web of Science ®Google Scholar
• Chen T, Da Fonseca C, Schönthal A. Intranasal perillyl alcohol for glioma therapy: molecular mechanisms and clinical development. Int J Mol Sci. 2018;19:3905.
   Web of Science ®Google Scholar
• Chaudhary S, Alam M, Siddiqui M, et al. Perillyl alcohol attenuates Ras-ERK signaling to inhibit murine skin inflammation and tumorigenesis. Chem Biol Interact. 2009;179:145–153.
   PubMed Web of Science ®Google Scholar
• Garcia D, Amorim L, de Castro Faria M, et al. The anticancer drug perillyl alcohol is a Na/K-ATPase inhibitor. Mol Cell Biochem. 2010;345:29–34.
   PubMed Web of Science ®Google Scholar
• Gomes A, Mello A, Ribeiro M, et al. Perillyl alcohol, a pleiotropic natural compound suitable for brain tumor therapy, targets free radicals. Arch Immunol Ther Exp (Warsz). 2017;65:285–297.
   PubMed Web of Science ®Google Scholar
• Cafardi J, Elmets C. T4 endonuclease V: review and application to dermatology. Expert Opin Biol Ther. 2008;8:829–838.
   PubMed Web of Science ®Google Scholar
• Yarosh D, Klein J, O’Connor A, et al. Effect of topically applied T4 endonuclease V in liposomes on skin cancer in xeroderma pigmentosum: a randomised study. Xeroderma pigmentosum study group. Lancet. 2001;357:926–929.
   PubMed Web of Science ®Google Scholar
• Micali G, Lacrrubba F, Nasca M, et al. Topical pharmacotherapy for skin cancer: part I. Pharmacology. J Am Acad Dermatol. 2014;70:965.e1-12.
   Web of Science ®Google Scholar
• Cuevas Sanchez P, Espinoza W, Pérez C, et al. Topical treatment of actinic keratoses with potassium dobesilate 5% cream. a preliminary open-label study. Eur J Med Res. 2011;16:67–70.
   PubMed Web of Science ®Google Scholar
• Minocha R, Damian DL, Halliday GM. Melanoma and nonmelanoma skin cancer chemoprevention: a role for nicotinamide? Photodermatol Photoimmunol Photomed. 2018;34:5–12.
   PubMed Web of Science ®Google Scholar
• Gensler HL, Williams T, Huang AC, et al. Oral niacin prevents photocarcinogenesis and photoimmunosuppression in mice. Nutr Cell. 1999;34:36–41.
   Google Scholar
• Damian DL. Photoprotective effects of nicotinamide. Photochem Photobiol Sci. 2010;9:578–585.
   PubMed Web of Science ®Google Scholar
• Arenberger P, Arenbergerova M. New and current preventive treatment options in actinic keratosis. Eur Acad Dermatol Venereol. 2017;31: Suppl 5:13–17.
   PubMedGoogle Scholar
• Drago F, Ciccarese G, Cogorno L, et al. Prevention of non-melanoma skin cancers with nicotinamide in transplant recipients: a case-control study. Eur J Dermatol. 2017;27:382–385.
   PubMed Web of Science ®Google Scholar
• Surjana D, Halliday GM, Martin AJ, et al. Oral nicotinamide reduces actinic keratoses in phase II double-blinded randomized controlled trials. J Invest Dermatol. 2012;132:1497–1500.
   PubMed Web of Science ®Google Scholar
• Bierman AS, Tinetti ME. Precision medicine to precision care: managing multimorbidity. Lancet. 2016;388:2721–2723.
   PubMed Web of Science ®Google Scholar
• Campione E, Di Prete M, Del Principe I, et al. Lack of efficacy of imiquimod in patients with basal cell carcinoma previously treated with rituximab for B cell lymphoma: two case reports. J Med Case Rep. 2016;10:57.
   PubMedGoogle Scholar
• Dika E, Vaccari S, Fanti PA, et al. Pain evaluation in patients affected by cutaneous squamous cell carcinoma and actinic keratosis: an observational study. G Ital Dermatol Venereol. 2017;152:413–417.
   PubMed Web of Science ®Google Scholar
• Basile J, Thiers B, Maize J, et al. Chemokine receptor expression in non-melanoma skin cancer. J Cutan Pathol. 2008;35:623–629.
   PubMed Web of Science ®Google Scholar
• NCCN Guidelines Version 2.2018. Squamous Cell Skin Cancer. https://oncolife.com.ua/doc/nccn/Squamous_Cell_Skin_Cancer.pdf
   Google Scholar
• Gee J, Saltzstein D, Kim K, et al. A phase II randomized, double-blind, presurgical trial of polyphenon E in bladder cancer patients to evaluate pharmacodynamics and bladder tissue biomarkers. Cancer Prev Res (Phila). 2017; 17AD;10:298–3007.
   PubMed Web of Science ®Google Scholar
• Mukhtar H, Ahmad N. Green tea in chemoprevention of cancer. Toxicol Sci. 1999;52:111–117.
   PubMed Web of Science ®Google Scholar
• Stockfleth E, Meyer T. The use of sinecatechins (polyphenon E) ointment for treatment of external genital warts. Expert Opin Biol Ther. 2012;12:783–793.
   PubMed Web of Science ®Google Scholar
• Stockfleth E, Meyer T. Sinecatechins (Polyphenon E) ointment for treatment of external genital warts and possible future indications. Expert Opin Biol Ther. 2014;14:1033–1043.
   PubMed Web of Science ®Google Scholar