We have developed transgenic mouse lines that are susceptible to the development of melanoma. These mice provide a model system for evaluating chemopreventive agents because they exhibit the necessary characteristics: a high incidence of tumor development, a moderate latency period and progressive stages of tumor development. We have demonstrated that the chemical carcinogen, 7, 12-dimethylbenz[a]anthracene and the environmental carcinogen, UV irradiation (280-340 nm), will cause melanoma in the TPras transgenic mice. The melanoma from DMBA-treated mice exhibit genetic and chromosomal alterations similar to those described for human melanomas. Using TPras transgenic mouse lines as our models, we propose to test the hypothesis that certain chemopreventive agents will prevent DMBA- and/or UV-induced melanoma by protecting against DNA damage or modulating the ras signaling pathway. Activation of upstream and downstream events in the ras pathways have been demonstrated as necessary for proliferation of melanocytes. In addition ras mutations have been observed in about 25% of the melanoma that developed in sun-exposed sites.
The specific aims that will be pursued to address our hypothesis are: 1) to evaluate the effects of retinoids (tretinoin, panretinin), perillyl alcohol (PA), epigallocatechin gallate (EGCG), and alpha-difluoromethylornithine (DFMO) on melanoma development in the Tpras transgenic mouse models. We will asses the effect of preventive agents on development of premalignant lesions, tumors, latency period, size and number of tumors, and metastatic spread; 2) To study which chemopreventive agents may prevent or block UV- induced DNA damage in melanocytes. In particular, we will examine the effects of the above agents on formation of pyrimidine dimers and the generation of reactive oxygen species; and 3) To investigate the effects of retinoids, PA, and DFMO in UV-induced epigenetic effects in melanocytes, specifically activation of the ras pathway. We will monitor activation/farnesylation of G-proteins, and AP-1 activity. Biological activities in melanocytes associated with activation of the ras pathway include proliferation as well as induction of apoptosis. These preclinical studies are designed to lead to the development of new chemopreventive strategies for human melanoma skin cancers.
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| 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 |
| 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 |
| 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 |
| 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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