The overall goal of this Program Project is to develop safe and highly efficacious intervention strategies for prevention of melanoma and 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. Approximately 60% of squamous cell carcinomas (SCC) arise from pre-existing actinic keratoses (AKs) and/or contiguous skin surfaces. 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 this Project we propose to conduct two phase IIb randomized placebo-controlled double-blinded, cancer prevention clinical trials in individuals with preclinical AKs. The chemoprevention agents to be used are those identified in prior phase IIb studies as well as in our current Projects. Recently, in a phase III trial in 2297 participants with greater than or equal to 100 AKs, we found that daily supplementation of 25,000 IU of oral vitamin A for 5 years was effective in preventing SCC [hazard ratio of o.74 (95% C.I.: 0.56 - 0.99, p = 0.04) for a few SCC, comparing subjects receiving vitamin A versus placebo]. In this study , oral vitamin A (retinyl palmitate) at 25,00 IU/day and 50,000 IU/day (doses which proved non-toxic in our previous phase IIa study) will be compared to topical 0.1 tretinoin administered for 6 months. In this study, topical tretinoin will be used as a positive control in comparison to two topical chemoprevention agents identified by the results of a concurrent of Project difluoromethylornithine (DFMO), epigallocatechin gallate (EGCG); 9-cis-retinoic acid; or perillyl alcohol. We propose to demonstrate that specific histopathologic and morphometric abnormalities, genetic alterations, and immunohistochemical surrogate endpoint biomarker (SEB) changes can be modulated safely by chemoprevention agents. 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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