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.
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.
| Blohm-Mangone, Karen; Burkett, Nichole B; Tahsin, Shekha et al. (2018) Pharmacological TLR4 Antagonism Using Topical Resatorvid Blocks Solar UV-Induced Skin Tumorigenesis in SKH-1 Mice. Cancer Prev Res (Phila) 11:265-278 |
| Knights-Mitchell, Shellie S; Romanowski, Marek (2018) Near-Infrared Activated Release of Doxorubicin from Plasmon Resonant Liposomes. Nanotheranostics 2:295-305 |
| Roh, Eunmiri; Lee, Mee-Hyun; Zykova, Tatyana A et al. (2018) Targeting PRPK and TOPK for skin cancer prevention and therapy. Oncogene 37:5633-5647 |
| Yamamoto, Hiroyuki; Ryu, Joohyun; Min, Eli et al. (2017) TRAF1 Is Critical for DMBA/Solar UVR-Induced Skin Carcinogenesis. J Invest Dermatol 137:1322-1332 |
| Zykova, Tatyana A; Zhu, Feng; Wang, Lei et al. (2017) The T-LAK Cell-originated Protein Kinase Signal Pathway Promotes Colorectal Cancer Metastasis. EBioMedicine 18:73-82 |
| Einspahr, Janine G; Curiel-Lewandrowski, Clara; Calvert, Valerie S et al. (2017) Protein activation mapping of human sun-protected epidermis after an acute dose of erythemic solar simulated light. NPJ Precis Oncol 1: |
| Gao, Ge; Zhang, Tianshun; Wang, Qiushi et al. (2017) ADA-07 Suppresses Solar Ultraviolet-Induced Skin Carcinogenesis by Directly Inhibiting TOPK. Mol Cancer Ther 16:1843-1854 |
| Chen, Yin; Vasquez, Monica M; Zhu, Lingxiang et al. (2017) Effects of Retinoids on Augmentation of Club Cell Secretory Protein. Am J Respir Crit Care Med 196:928-931 |
| Glazer, Evan S; Bartels, Peter H; Lian, Fangru et al. (2016) Quantitative histopathology identifies patients with thin melanomas who are at risk for metastases. Melanoma Res 26:261-6 |
| Franklin, Stephen J; Younis, Usir S; Myrdal, Paul B (2016) Estimating the Aqueous Solubility of Pharmaceutical Hydrates. J Pharm Sci 105:1914-1919 |
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