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 #
5P01CA027502-31
Application #
8689922
Study Section
Special Emphasis Panel (ZCA1-GRB-P)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
31
Fiscal Year
2014
Total Cost
$205,226
Indirect Cost
$64,845
Name
University of Arizona
Department
Type
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Dickinson, Sally E; Rusche, Jadrian J; Bec, Sergiu L et al. (2015) The effect of sulforaphane on histone deacetylase activity in keratinocytes: Differences between in vitro and in vivo analyses. Mol Carcinog 54:1513-20
Glazer, Evan S; Hornbrook, Mark C; Krouse, Robert S (2014) A meta-analysis of randomized trials: immediate stent placement vs. surgical bypass in the palliative management of malignant biliary obstruction. J Pain Symptom Manage 47:307-14
Williams, Joshua D; Bermudez, Yira; Park, Sophia L et al. (2014) Malondialdehyde-derived epitopes in human skin result from acute exposure to solar UV and occur in nonmelanoma skin cancer tissue. J Photochem Photobiol B 132:56-65
Sheng, Yuqiao; Li, Wei; Zhu, Feng et al. (2014) 3,6,2',4',5'-Pentahydroxyflavone, an orally bioavailable multiple protein kinase inhibitor, overcomes gefitinib resistance in non-small cell lung cancer. J Biol Chem 289:28192-201
Lim, Tae-Gyu; Lee, Sung-Young; Huang, Zunnan et al. (2014) Curcumin suppresses proliferation of colon cancer cells by targeting CDK2. Cancer Prev Res (Phila) 7:466-74
Wen, W; Peng, C; Kim, M O et al. (2014) Knockdown of RNF2 induces apoptosis by regulating MDM2 and p53 stability. Oncogene 33:421-8
Lim, Do Young; Lee, Mee-Hyun; Shin, Seung Ho et al. (2014) (+)-2-(1-Hydroxyl-4-oxocyclohexyl) ethyl caffeate suppresses solar UV-induced skin carcinogenesis by targeting PI3K, ERK1/2, and p38. Cancer Prev Res (Phila) 7:856-65
Yao, Ke; Chen, Hanyong; Liu, Kangdong et al. (2014) Kaempferol targets RSK2 and MSK1 to suppress UV radiation-induced skin cancer. Cancer Prev Res (Phila) 7:958-67
Dickinson, Sally E; Olson, Erik R; Levenson, Corey et al. (2014) A novel chemopreventive mechanism for a traditional medicine: East Indian sandalwood oil induces autophagy and cell death in proliferating keratinocytes. Arch Biochem Biophys 558:143-52
Franklin, Stephen J; Dickinson, Sally E; Karlage, Kelly L et al. (2014) Stability of sulforaphane for topical formulation. Drug Dev Ind Pharm 40:494-502

Showing the most recent 10 out of 348 publications