UV-Induced Epigenetic Field Effect as a Target for Melanoma Therapy and Prevention
Abstract
This proposal addresses the Fiscal Year 2015 (FY15) Peer Reviewed Cancer Research Program (PRCRP) Topic Area of Melanoma, and the FY15 PRCRP Military Relevant Focus Areas of "risk factors and environmental carcinogens" as well as "gaps in cancer prevention." Melanoma is the deadliest skin cancer that is rapidly rising in incidence, and is notoriously aggressive and chemoresistant. Despite ultraviolet radiation (UV or UVR) being implicated as a direct cause of as many as 85% of melanoma, the molecular mechanisms remain largely elusive. The highest risk is associated with intermittent erythemal exposures to UV during childhood. How do these early-life exposures increase the risk for melanomagenesis decades later is a profound mystery. We posit that identification of early UV-induced molecular events that render melanocytes susceptible to subsequent melanomagenesis will provide novel targets for melanoma prevention and therapy. The focus of the search for melanoma-initiating events has long been UV-induced DNA mutations, albeit with limited success. Although a large number of mutations have been identified in melanoma tissues, it is unclear whether any of these play a driver role in the earliest phases of the melanoma-initiating molecular cascade. We believe that it is time to think out of the box and explore other mechanisms of UV-induced initiation of melanoma. In this context, the role of UV-induced epigenetic modulations remains underappreciated and unexplored. The overall goal of this proposal is to discover novel epigenetic biomarkers of UV-induced melanoma susceptibility as well as targets for personalized prevention and therapeutics. The melanoma incidence rate is significantly greater in military personnel older than 45 than in the general population. This is likely due to extended deployments in areas of high UVR. A recent study presented at the World Congress on Cancers of the Skin (2014) showed that 77% of military personnel reported more than 4 hours of daily sun exposure, with only 27% having regular access to sunscreen, and consequently 68% reported being sunburned. Moreover, both military and civilian pilots, who tend to get greater UVR exposure, exhibit higher melanoma incidence. Despite recent successes in melanoma therapeutics, rapid resistance and recurrence remain a big challenge in the clinic for both military and civilian patients. Thus, the need for identification of new biomarkers of risk assessment and targets for melanoma preventive and therapeutic strategies is as urgent as ever. However, these goals are hampered by major gaps in our knowledge about how solar or artificial UVR initiates melanoma. There are still considerable questions about UVR-induced DNA mutations as the melanoma-initiating events. The studies proposed here will open new avenues of investigation in the field and will contribute significantly towards resolving some of the long-standing mechanistic questions surrounding the underlying molecular mechanisms of UVR-induced melanomagenesis. These studies will potentially identify new epigenetic biomarkers for excessive sun exposure, which will be useful to accurately assess an individual s risk of developing melanoma, leading to personalized preventive and therapeutic strategies. Specifically, these studies will provide proof of principle for epigenetic drug intervention as a viable preventive and therapeutic strategy against UVR-induced melanoma. In the short term, we anticipate to identify novel epigenetic biomarkers that would be useful for identification of high-risk military personnel who have acquired excessive sun exposure during deployments and are at higher risk for developing melanoma. These personnel would be candidates for enhanced melanoma surveillance in the dermatology clinic. These studies will also provide proof of principle for preclinical and subsequently clinical studies for epigenetic drug intervention as a preventive measure by reversin
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610177
Entities
People
- M. Raza Zaidi
Organizations
- Temple University
- United States Army