{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T21:06:46Z","timestamp":1762981606957,"version":"3.40.5"},"reference-count":47,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T00:00:00Z","timestamp":1686614400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Experimental Dermatology"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Each year, 3.3 million Americans are diagnosed with non\u2010melanoma skin cancers (NMSC) and an additional 40 million individuals undergo treatment of precancerous actinic keratosis lesions. The most effective treatments of NMSC (surgical excision and Mohs surgery) are invasive, expensive and require specialised training. More readily accessible topical therapies currently are 5\u2010fluorouracil (a chemotherapeutic agent) and imiquimod (an immune modulator), but these can have significant side effects which limit their efficacy. Therefore, more effective and accessible treatments are needed for non\u2010melanoma cancers and precancers. Our previous work demonstrated that the small molecule N\u2010phosphonacetyl\u2010L\u2010aspartate (PALA) both inhibits pyrimidine nucleotide synthesis and activates pattern recognition receptor nucleotide\u2010binding oligomerization domain 2. We propose that topical application of PALA would be an effective NMSC therapy, by combining the chemotherapeutic and immune modulatory features of 5\u2010fluorouracil and imiquimod. Daily topical application of PALA to mouse skin was well tolerated and resulted in less irritation, fewer histopathological changes, and less inflammation than caused by either 5\u2010fluorouracil or imiquimod. In an ultraviolet light\u2010induced NMSC mouse model, topical PALA treatment substantially reduced the numbers, areas and grades of tumours, compared to vehicle controls. This anti\u2010neoplastic activity was associated with increased expression of the antimicrobial peptide cathelicidin and increased recruitment of CD8<jats:sup>+<\/jats:sup> T cells and F4\/80<jats:sup>+<\/jats:sup> macrophages to the tumours, demonstrating both immunomodulatory and anti\u2010proliferative effects. These findings indicate that topical PALA is an excellent candidate as an effective alternative to current standard\u2010of\u2010care NMSC therapies.<\/jats:p>","DOI":"10.1111\/exd.14853","type":"journal-article","created":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T08:20:01Z","timestamp":1686644401000},"page":"1485-1497","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Topical <i>N<\/i>\u2010phosphonacetyl\u2010<scp>l<\/scp>\u2010aspartate is a dual action candidate for treating non\u2010melanoma skin cancer"],"prefix":"10.1111","volume":"32","author":[{"given":"Kala K.","family":"Mahen","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University  Cleveland Ohio USA"},{"name":"Department of Cancer Biology Lerner Research Institute, Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lilian","family":"Markley","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University  Cleveland Ohio USA"},{"name":"Department of Inflammation &amp; Immunity Lerner Research Institute, Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jolie","family":"Bogart","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology Lerner Research Institute, Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hope","family":"Klatka","sequence":"additional","affiliation":[{"name":"Department of Inflammation &amp; Immunity Lerner Research Institute, Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vijay","family":"Krishna","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University  Cleveland Ohio USA"},{"name":"Department of Biomedical Engineering Lerner Research Institute, Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward V.","family":"Maytin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Lerner Research Institute, Cleveland Clinic  Cleveland Ohio USA"},{"name":"Department of Dermatology Dermatology and Plastic Surgery Institute, Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George R.","family":"Stark","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University  Cleveland Ohio USA"},{"name":"Department of Cancer Biology Lerner Research Institute, Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6745-9487","authenticated-orcid":false,"given":"Christine","family":"McDonald","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University  Cleveland Ohio USA"},{"name":"Department of Inflammation &amp; 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