The hypothesis in this Project is that the Pl-3 kinase-Akt-mTOR and the AMP-activated protein kinase (i.e. AMPK)-mTOR signaling pathways are targets forthe development of topical chemoprevention agents to inhibit solar UV induced non-melanoma skin cancer by blocking the growth of or inducing the death of genetically altered and solar UV-initiated keratinocytes.
Specific Aim 1 : To use genetically modified mice to determine the functional roles of Akt-1 and mTOR in solar UV-induced mouse skin carcinogenesis. The experimental approach is to develop epidermis specific inducible, conditional knockout mice for Akt-1 and mTOR and use these mice to validate these molecular targets. These mice will be given to Project 2 to study cross talk between the Akt/mTOR and Fyn/RSK2 pathways.
Specific Aim 2 : To use genetically modified mice to determine the functional role of AMPK in solar UV-induced mouse skin carcinogenesis. The experimental approach Is to develop transgenic mice where constitutively active AMPK is specifically expressed in the epidermis and use these mice to validate the molecular target.
Specific Aim 3 : To utilize inhibitors of Akt and mTOR as well as AMPK activators independently or in combination to determine whether pharmacological modulation of these kinases inhibits solar UV-induced mTOR signaling, cell proliferation, anti-apoptotic signaling and skin carcinogenesis. The Akt inhibitor to be used is PHT-427. The mTOR Inhibitor is rapamycin and the AMPK activator is Metformin, In collaboration with Project 2 we will test combinations of drugs targeting the Akt/mTOR and Fyn/RSK2 signaling pathways Specific Aim 4: To crossvalidate Akt, mTOR and AMPK as molecular targets for the chemoprevention of solar UV-induced skin cancer between mouse and human skin using tissue microarrays and reverse phase protein microarrays.
This aim will be carried out in collaboration with Project 3 and will involve solar light-irradiation of subjects and punch biopsies to be used for studying the activation of the target signaling pathways. Successful lead drugs or drug combinations that show chemoprevention activity in this preclinical Project will be tested in the clinic by Project 3. 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 of the 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 the development of skin cancer which is associated with chronic sun exposure. New agents to be applied to the skin will be developed and used in combination with sun screens. The successful completion of this Project can lead to a decrease in the incidence of skin cancer which accounts for approximately 40%) of all new cancers diagnosed in the US.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA027502-30
Application #
8504933
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
$187,100
Indirect Cost
$59,650
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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