Non-melanoma skin cancers (NMSCs; cutaneous basal cell carcinomas and squamous cell carcinomas) are the most common malignancies in humans in the United States. They are the source of considerable morbidity and are a tremendous cost to the health care system. Current methods for their prevention have consisted primarily of sun and tanning bed avoidance and the regular use of sunscreens. Unfortunately, these measures have proven inadequate, and in contrast to most other malignancies, the incidence of NMSCs continues to increase. Two agents that show promise for the prevention of non-melanoma skin cancers are non-steroidal anti-inflammatory agents (NSAIDs), which inhibit the cyclooxygenase enzyme, and difluoromethylornithine (DFMO), a non-competitive inhibitor of the enzyme ornithine decarboxylase. In other organ systems, these agents have synergistic cancer chemopreventive activities. Because the skin is readily accessible, it may be possible to apply topical formulations of these agents for the chemoprevention of skin cancers without encountering the potential for systemic toxicity. We hypothesize that topical application of the COX inhibitor diclofenac and/or topical DFMO for 9 months is a safe and effective method of reversing biomarkers associated with the development of non-melanoma skin cancers in subjects at risk for their development and will prevent the onset of new actinic keratoses. To test our hypothesis, we plan to conduct a randomized, double-blind, placebo-controlled trial of 100 subjects with a history of basal cell and/or squamous cell skin cancer and at least 8 actinic keratoses. Patients will be randomized to receive: topical DFMO + placebo; placebo + topical diclofenac; topical DFMO + topical diclofenac; placebo + placebo. We will assess whether topical DFMO + topical diclofenac alters skin biomarkers focusing on prostaglandin E2, polyamines and ornithine decarboxylase, proliferation and apoptosis markers (Ki67, PCNA, cyclin D1, caspase 3, tunel assay, Bcl-2, Bax), and molecules in the Akt/ERK1/2 axis. Studies are planned to determine if treatment with topical DFMO and/or topical diclofenac is well-tolerated without signs of significant toxicity. We will also assess whether subjects randomized to topical diclofenac and/or topical DFMO develop over a 9 month period of time fewer new actinic keratoses than those who are placed on placebo. The ultimate goal of these studies will be to determine whether topical diclofenac and/or DFMO should be evaluated in a clinical trial for the prevention of non-melanoma skin cancers.
Studies are proposed in this application that will evaluate 1) the effect of two topical agents (diclofenac and/or difluoromethylornithine) on biomarkers associated with basal cell and squamous cell carcinoma of the skin, and 2) their safety and efficacy in the prevention of actinic keratoses, a precursor of non-melanoma skin cancer. The new knowledge obtained from this study will provide valuable information about the utility of using topical medications as chemopreventive agents for the prevention of skin cancers, which is a necessary precondition for broader, more definitive prevention testing of their efficacy in preventing non-melanoma skin cancers.
|Sharma, Pooja; Montes de Oca, Mary K; Alkeswani, Amena R et al. (2018) Tea polyphenols for the prevention of UVB-induced skin cancer. Photodermatol Photoimmunol Photomed 34:50-59|
|Slominski, Andrzej T; Bro?yna, Anna A; Skobowiat, Cezary et al. (2018) On the role of classical and novel forms of vitamin D in melanoma progression and management. J Steroid Biochem Mol Biol 177:159-170|
|Bakshi, Anshika; Chaudhary, Sandeep C; Rana, Mehtab et al. (2017) Basal cell carcinoma pathogenesis and therapy involving hedgehog signaling and beyond. Mol Carcinog 56:2543-2557|
|Nasti, Tahseen H; Cochran, J Barry; Vachhani, Raj V et al. (2017) IL-23 Inhibits Melanoma Development by Augmenting DNA Repair and Modulating T Cell Subpopulations. J Immunol 198:950-961|
|Kohli, Indermeet; Shafi, Rubina; Isedeh, Prescilia et al. (2017) The impact of oral Polypodium leucotomos extract on ultraviolet B response: A human clinical study. J Am Acad Dermatol 77:33-41.e1|
|Ahmad, Israr; Guroji, Purushotham; DeBrot, Amanda H et al. (2017) Loss of INK4a/Arf gene enhances ultraviolet radiation-induced cutaneous tumor development. Exp Dermatol 26:1018-1025|
|Chaudhary, Sandeep C; Waseem, Mohammad; Rana, Mehtab et al. (2017) Naproxen Inhibits UVB-induced Basal Cell and Squamous Cell Carcinoma Development in Ptch1+/- /SKH-1 Hairless Mice. Photochem Photobiol 93:1016-1024|
|Burns, Erin M; Guroji, Purushotham; Ahmad, Israr et al. (2017) Association of Vitamin D Receptor Polymorphisms With the Risk of Nonmelanoma Skin Cancer in Adults. JAMA Dermatol :|
|Slominski, Andrzej T; Bro?yna, Anna A; Zmijewski, Michal A et al. (2017) Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management. Lab Invest 97:706-724|
|Pal, Harish Chandra; Hunt, Katherine Marchiony; Diamond, Ariana et al. (2016) Phytochemicals for the Management of Melanoma. Mini Rev Med Chem 16:953-79|
Showing the most recent 10 out of 13 publications