The candidate has a doctorate in Biochemistry and Molecular Biology with extensive experience in using mouse models to perform basic cancer research. During his postdoctoral fellowship, the candidate has generated a novel mouse model that has allowed new insights into how ultraviolet radiation (UV) may cause development of melanoma, the deadliest form of skin cancer. He has made an important discovery that interferon (IFN)-gamma, a signaling protein involved in immunological functions and conventionally thought to be anti-tumorigenesis, may under some circumstances aid the outgrowth and progression of UV- induced melanoma. This high-impact research has formed the basis for the research proposed in this application. The candidate's immediate goal is to elucidate the molecular mechanism(s) of the pro- melanomagenic role of IFN-gamma, and to explore whether inhibition of IFN-gamma could be used as an anti- melanoma therapeutic and/or preventive strategy. In the long-term, the candidate wants to focus on the delineation of the molecular mechanisms of UV-induced melanoma initiation and progression. Environment: The candidate is currently a postdoctoral research fellow in the Laboratory of Cancer Biology and Genetics at the National Cancer Institute, and is seeking an independent research faculty position in an academic or non-profit research institution. He has set up collaborations with a world-class team of scientists with relevant expertise to advise throughout this project, ensuring timely conclusion and high-impact outcome. Research: The candidate has proposed a paradigm-shifting hypothesis that IFN-gamma plays a pro- tumorigenic role in the context of UVB-induced melanomagenesis. The proposed research will elucidate the molecular mechanisms of the pro-melanomagenic effects of IFN-gamma, and will explore whether inhibition of IFN-gamma pathway is a viable treatment and/or preventive strategy for human melanoma.
In Specific Aim 1, UV-induced melanomagenesis experiments will be performed in a mouse model of UVB-induced melanomagenesis in the IFN-gamma knockout genetic background to test whether IFN-gamma is required for melanomagenesis.
Specific Aim 2 will elucidate the downstream target genes of IFN-gamma signaling that mediate the pro-melanomagenic effects of IFN-gamma, using both human and mouse melanoma cell lines. The applicability of the results will be validated in human melanoma cell lines and tissues. In Specifi Aim 3, novel peptide-based IFN-gamma inhibiting compounds will be validated and tested for their efficacy in preventing UVB-induced melanomagenesis and treating established melanomas in mouse models. It is anticipated that the results obtained from the proposed research will provide significant new translational opportunities for prevention and treatment of human melanoma.
Melanoma is one of the deadliest cancers whose incidence continues to rise rapidly in the USA. Although exposure to the ultraviolet radiation from sun is accepted to be the greatest risk factor for melanoma, the molecular mechanisms of this cause and effect relationship remain unclear. The proposed research will help narrow this gap in knowledge about the underlying molecular causes of melanoma and will provide new potential therapeutic targets for the treatment and prevention of melanoma. Furthermore, these studies will identify potential biomarkers for excessive sun exposure, which will be useful for accurately assessing an individual's risk of developing melanoma and may lead to effective prognostic strategies.
|Pérez-Guijarro, Eva; Day, Chi-Ping; Merlino, Glenn et al. (2017) Genetically engineered mouse models of melanoma. Cancer 123:2089-2103|
|Vultur, Adina; O'Connell, Michael; Webster, Marie et al. (2014) Meeting report from the 10th International Congress of the Society for Melanoma Research, Philadelphia, PA, November 2013. Pigment Cell Melanoma Res 27:E1-E12|