Program Official

Principal Investigator

Craig A
Elmets
Awardee Organization

University Of Alabama At Birmingham
United States

Fiscal Year
2022
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Topical Chemoprevention of Skin Cancer Biomarkers

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.

Publications

  • Nasti TH, Yusuf N, Sherwani MA, Athar M, Timares L, Elmets CA. Regulatory T Cells Play an Important Role in the Prevention of Murine Melanocytic Nevi and Melanomas. Cancer prevention research (Philadelphia, Pa.). 2021 Feb;14(2):165-174. Epub 2020 Nov 4. PMID: 33148679
  • Elmets CA, Slominski A, Athar M. The Challenge of Melanoma Chemoprevention. Cancer prevention research (Philadelphia, Pa.). 2022 Feb;15(2):71-74. Epub 2022 Jan 13. PMID: 35027465
  • Chaudhary SC, Waseem M, Rana M, Xu H, Kopelovich L, Elmets CA, Athar M. Naproxen Inhibits UVB-induced Basal Cell and Squamous Cell Carcinoma Development in Ptch1+/- /SKH-1 Hairless Mice. Photochemistry and photobiology. 2017 Jul;93(4):1016-1024. Epub 2017 May 9. PMID: 28329421
  • Bakshi A, Shafi R, Nelson J, Cantrell WC, Subhadarshani S, Andea A, Athar M, Elmets CA. The clinical course of actinic keratosis correlates with underlying molecular mechanisms. The British journal of dermatology. 2020 Apr;182(4):995-1002. Epub 2019 Sep 11. PMID: 31299087
  • Slominski RM, Raman C, Elmets C, Jetten AM, Slominski AT, Tuckey RC. The significance of CYP11A1 expression in skin physiology and pathology. Molecular and cellular endocrinology. 2021 Jun 15;530:111238. Epub 2021 Mar 12. PMID: 33716049
  • Pal HC, Diamond AC, Strickland LR, Kappes JC, Katiyar SK, Elmets CA, Athar M, Afaq F. Fisetin, a dietary flavonoid, augments the anti-invasive and anti-metastatic potential of sorafenib in melanoma. Oncotarget. 2016 Jan 12;7(2):1227-41. PMID: 26517521
  • Bakshi A, Chaudhary SC, Rana M, Elmets CA, Athar M. Basal cell carcinoma pathogenesis and therapy involving hedgehog signaling and beyond. Molecular carcinogenesis. 2017 Dec;56(12):2543-2557. Epub 2017 Aug 22. PMID: 28574612
  • Berman B, Ellis C, Elmets C. Polypodium Leucotomos--An Overview of Basic Investigative Findings. Journal of drugs in dermatology : JDD. 2016 Feb;15(2):224-8. PMID: 26885792
  • Kohli I, Shafi R, Isedeh P, Griffith JL, Al-Jamal MS, Silpa-Archa N, Jackson B, Athar M, Kollias N, Elmets CA, Lim HW, Hamzavi IH. The impact of oral Polypodium leucotomos extract on ultraviolet B response: A human clinical study. Journal of the American Academy of Dermatology. 2017 Jul;77(1):33-41.e1. Epub 2017 Mar 22. PMID: 28341348
  • Slominski AT, Brożyna AA, Skobowiat C, Zmijewski MA, Kim TK, Janjetovic Z, Oak AS, Jozwicki W, Jetten AM, Mason RS, Elmets C, Li W, Hoffman RM, Tuckey RC. On the role of classical and novel forms of vitamin D in melanoma progression and management. The Journal of steroid biochemistry and molecular biology. 2018 Mar;177:159-170. Epub 2017 Jul 1. PMID: 28676457
  • Pal HC, Hunt KM, Diamond A, Elmets CA, Afaq F. Phytochemicals for the Management of Melanoma. Mini reviews in medicinal chemistry. 2016;16(12):953-79. PMID: 26864554
  • Ahmad I, Guroji P, DeBrot AH, Manapragada PP, Katiyar SK, Elmets CA, Yusuf N. Loss of INK4a/Arf gene enhances ultraviolet radiation-induced cutaneous tumor development. Experimental dermatology. 2017 Nov;26(11):1018-1025. Epub 2017 Jul 9. PMID: 28418604
  • Burns EM, Guroji P, Ahmad I, Nasr HM, Wang Y, Tamimi IA, Stiefel E, Abdelgawwad MS, Shaheen A, Muzaffar AF, Bush LM, Hurst CB, Griffin RL, Elmets CA, Yusuf N. Association of Vitamin D Receptor Polymorphisms With the Risk of Nonmelanoma Skin Cancer in Adults. JAMA dermatology. 2017 Oct 1;153(10):983-989. PMID: 28832880
  • Sharma P, Montes de Oca MK, Alkeswani AR, McClees SF, Das T, Elmets CA, Afaq F. Tea polyphenols for the prevention of UVB-induced skin cancer. Photodermatology, photoimmunology & photomedicine. 2018 Jan;34(1):50-59. Epub 2017 Nov 20. PMID: 29044724
  • Slominski AT, Brożyna AA, Zmijewski MA, Jóźwicki W, Jetten AM, Mason RS, Tuckey RC, Elmets CA. Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management. Laboratory investigation; a journal of technical methods and pathology. 2017 Jun;97(6):706-724. Epub 2017 Feb 20. PMID: 28218743
  • Slominski AT, Slominski RM, Raman C, Chen JY, Athar M, Elmets C. Neuroendocrine signaling in the skin with a special focus on the epidermal neuropeptides. American journal of physiology. Cell physiology. 2022 Dec 1;323(6):C1757-C1776. Epub 2022 Nov 1. PMID: 36317800
  • Wu L, Chaudhary SC, Atigadda VR, Belyaeva OV, Harville SR, Elmets CA, Muccio DD, Athar M, Kedishvili NY. Retinoid X Receptor Agonists Upregulate Genes Responsible for the Biosynthesis of All-Trans-Retinoic Acid in Human Epidermis. PloS one. 2016 Apr 14;11(4):e0153556. doi: 10.1371/journal.pone.0153556. eCollection 2016. PMID: 27078158
  • Nasti TH, Cochran JB, Vachhani RV, McKay K, Tsuruta Y, Athar M, Timares L, Elmets CA. IL-23 Inhibits Melanoma Development by Augmenting DNA Repair and Modulating T Cell Subpopulations. Journal of immunology (Baltimore, Md. : 1950). 2017 Jan 15;198(2):950-961. Epub 2016 Dec 21. PMID: 28003381

Clinical Trials

Study Name Clinical Trial ID
Topical Diclofenac and Topical DFMO Chemoprevention Trial in Subjects With a History of Skin Cancer NCT04091022