Project 3 will test and clinically validate mechanisms and pharmacologic strategies explored in Projects 1-2, which target Akt-mTOR, AMPK-mTOR, and Fyn/RSK pathways. Advanced clinical/translational study of skin cancer carcinogenesis, biology, and pathophysiology will help reduce morbidity/ mortality, provide insight into keratinocyte signaling, and provide an easily-accessed human model of full-spectrum carcinogenesis for other epithelial cancers. The overall goal of this Program Project is to eradicate intraepithelial neoplasias (lEN) and substantially reduce the risk of squamous cell carcinoma. Our objectives are to determine clinical, histopathologic, karyometric, and protein/phosphoprotein activation patterns associated with human skin carcinogenesis and to develop safe, active drugs for skin cancer prevention. The hypothesis for this project is that topical small molecule drugs can modulate specific targets in solar UV-induced signaling cascades resulting in attenuation or reversal of skin sun damage.
Aims i nclude;1) To demonstrate and cross-validate signaling targets and pathways activated in chronically sun-exposed human skin;2) To validate signaling pathway modulation demonstrated by small molecule inhibitors in preclinical studies by acutely exposing human skin to solar simulated light;3) To demonstrate safety and tolerability of new topical drugs when applied to human skin;4) To demonstrate biomarker and epidermal target modulation by topical drugs applied to sun-damaged human skin;and 5) To demonstrate clinical benefit of topical drugs (especially drug combinations), and further validate biomarker selection in skin cancer chemoprevention trials. Developmental Aims include: 1) To further develop optical coherence tomography hardware and discriminative image-analysis software;and 2) To develop a "skin chip" for mRNA expression array analysis directly from fixed tissue using a quantitative nuclease protection assay. New strategies include use of solar simulated light instead of fractionated UVA or UVB;advanced reverse-phase protein microarray technology for molecular network analysis;and faster drug/target validation using "Phase 0" clinical trials. Translation of new topical drug/target discoveries will direct new individualized treatment of lEN In the skin. This highly interactive and clinically translational research program project focuses on the successful preclinical testing of targeted chemoprevention agents in Innovative mouse models (Projects 1 and 2) followed by the design and implementation of clinical trials in at-risk human populations (Project 3). Detailed descriptions ofthe decision-tree selection process as well as the interactions between Projects and Cores are found on the Resources Format Page.

Public Health Relevance

The intent of this Project is to develop new strategies to prevent skin cancer caused by long-term sun exposure. New drugs will be tested in clinical trials for the ability to treat sun damage and prevent or treat precancerous lesions. The successful completion of this Project can lead to new drugs that can lower the incidence of skin cancer, the most prevalent type of cancer in the U.S.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA027502-30
Application #
8504934
Study Section
Special Emphasis Panel (ZCA1-GRB-P)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
30
Fiscal Year
2013
Total Cost
$251,940
Indirect Cost
$59,649
Name
University of Arizona
Department
Type
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Dickinson, Sally E; Janda, Jaroslav; Criswell, Jane et al. (2016) Inhibition of Akt Enhances the Chemopreventive Effects of Topical Rapamycin in Mouse Skin. Cancer Prev Res (Phila) 9:215-24
Peng, C; Zeng, W; Su, J et al. (2016) Cyclin-dependent kinase 2 (CDK2) is a key mediator for EGF-induced cell transformation mediated through the ELK4/c-Fos signaling pathway. Oncogene 35:1170-9
Janda, Jaroslav; Burkett, Nichole B; Blohm-Mangone, Karen et al. (2016) Resatorvid-based Pharmacological Antagonism of Cutaneous TLR4 Blocks UV-induced NF-κB and AP-1 Signaling in Keratinocytes and Mouse Skin. Photochem Photobiol 92:816-825
Franklin, Stephen J; Younis, Usir S; Myrdal, Paul B (2016) Estimating the Aqueous Solubility of Pharmaceutical Hydrates. J Pharm Sci 105:1914-9
Kim, J-E; Roh, E; Lee, M H et al. (2016) Fyn is a redox sensor involved in solar ultraviolet light-induced signal transduction in skin carcinogenesis. Oncogene 35:4091-101
Jeter, Joanne M; Curiel-Lewandrowski, Clara; Stratton, Steven P et al. (2016) Phase IIB Randomized Study of Topical Difluoromethylornithine and Topical Diclofenac on Sun-Damaged Skin of the Forearm. Cancer Prev Res (Phila) 9:128-34
Franklin, Stephen J; Myrdal, Paul B (2015) Solid-State and Solution Characterization of Myricetin. AAPS PharmSciTech 16:1400-8
Curiel-Lewandrowski, Clara; Tang, Jean Y; Einspahr, Janine G et al. (2015) Pilot study on the bioactivity of vitamin d in the skin after oral supplementation. Cancer Prev Res (Phila) 8:563-9
Kim, Jong-Eun; Son, Joe Eun; Jeong, Hyein et al. (2015) A Novel Cinnamon-Related Natural Product with Pim-1 Inhibitory Activity Inhibits Leukemia and Skin Cancer. Cancer Res 75:2716-28
Bermudez, Yira; Stratton, Steven P; Curiel-Lewandrowski, Clara et al. (2015) Activation of the PI3K/Akt/mTOR and MAPK Signaling Pathways in Response to Acute Solar-Simulated Light Exposure of Human Skin. Cancer Prev Res (Phila) 8:720-8

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