The overall goal of this Program Project is to develop safe and highly efficacious intervention strategies for prevention of melanoma nd non- melanoma skin cancers (NMSC) and to develop basic science and clinical research approaches which will serve as models for the chemoprevention of a wide range of human epithelial cancers. In this Project, we propose to demonstrate that specific histopathologic and morphometric abnormalities, genetic alterations, and immunohistochemical surrogate endpoint biomarker (SEB) changes are associated with a multi-step progression from normal skin to NMSC or melanoma in human study participants and that these biomarkers can be modulated safely by novel topical chemoprevention agents. Approximately 60% of squamous cell carcinomas arise from pre- existing actinic keratoses (AKs) and /or under contiguous skin surfaces. AKs may represent a significant risk factor for melanoma as well. Additionally, case-control studies found that dysplastic nevi (DN) are the strongest risk factor for melanoma. In the first year of this grant, subjects with DN, SCC, AKs, and pre-clinical AKs will be recruited to document that specific histopathologic and morphometric abnormalities, genetic alterations and immunohistochemical biomarkers are associated with the progression from normal skin to AK to SCC and normal skin to DN to melanoma and that these biomarkers are reproducible for at least a three month time period. Researchers agree that the probability of successfully altering the natural history of any cancer increases by targeting an earlier, rather than a later, time point in carcinogenesis. Therefore, in years 2-5, subjects with preclinical AKs or DN will be recruited to conduct phase IIa randomized placebo-controlled cancer prevention clinical trials of topical agents including difluoromethylornithine (DFMO), epigallocatechin gallate (EGCG), 9-cis-retinoic acid perillyl alcohol and sodium salicylate. Agents selected must first be shown: 1) active in a mouse UVB carcinogenesis model and/or a transgenic mouse melanoma model; 2) locally and systematically non-toxic in murine models; and 3) able to penetrate full thickness skin from BALB/c mice and humans (i.e. face lift skin). During these clinical studies we will determine the predictive accuracy of ultraviolet and polarized photography with respect to identification of abnormal histopathologic and morphometric areas of forearm skin epidermis and, ultimately, examine the histopathologic/morphometric and molecular genetic pathogenesis of skin preneoplasia.
| 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 |
| 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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