Pharmacological Management of Ultraviolet Radiation-Induced Skin Cancer
Abstract
Ultraviolet B (UVB) radiation is largely responsible for the development of skin cancer. When UVB-induced DNA damage in cells is not repaired, it can lead to initiation of non-melanoma skin cancers. Xeroderma pigmentosum (XP) disease is caused by a defect in repair of damaged DNA. Toll-like receptor-4 (TLR4) and NLR family pyrin domain containing 3 (NLRP3) belong to the family of innate immune receptors and are highly expressed in skin tumors. We have shown that loss of TLR4 resulted in efficient repair of DNA damage in the skin of mice. We have also shown that TLR4-deficient mice develop fewer tumors in mice exposed to UVB radiation. Resatorvid (TAK-242) is a TLR4-sepcific pharmacological inhibitor that is being tested in clinical trials. We and others have shown that TAK-242 has been effective in inhibition of TLR4 in skin cells and mice after single exposure to UVB radiation. We have found that expression of NLRP3 is also reduced in skin cells treated with TAK-242. There is no information on the role of TAK-242 in DNA damage and prevention of UVB-induced skin tumors. This proposal addresses the mechanism elicited by which TLR4 inhibitor TAK-242 will prevent the development of UVB-induced skin tumors. We therefore propose that TAK-242 maybe highly effective in preventing UVB-induced non-melanoma skin cancer in mice by repair of UVB-induced DNA damage and inactivation of NLRP3 inflammasome in the skin. In this proposal, we will determine the mechanism through which TAK-242 regulates inflammation and prevents skin cancer. This proposal addresses the Topic Area of “Melanoma and other skin cancers.” Basal cell carcinomas (BCC) and squamous cell carcinomas (SCC), grouped together under the term nonmelanoma skin cancer (NMSC), are a major skin problem. In the United States, in contrast to most other cancers, which have either stabilized or begun to decline, the likelihood of developing a NMSC continues to grow. Moreover, NMSC are developing in younger and younger age groups. The epidemic of skin cancer represents a major public health issue and is a tremendous cost to healthcare systems in the United States and worldwide. The findings from this study will help establish the role of TLR4 inhibitor TAK-242 in prevention of DNA damage and development of skin cancer. This inhibitor is already in clinical trial for other diseases. For our purpose, we intend to use this inhibitor in cream based formulations along with sunscreens to prevent sunburns and pre-cancerous lesions so they do not develop skin cancer. After determining its safety and efficacy in animal models, we intend to move this inhibitor to the clinic and perform studies to evaluate its safety and efficacy in humans. My collaborator, Dr. Elmets, has extensive experience in performing these studies, and I have collaborated with him on some of his clinical trials. We have a well-equipped Dermatology clinic here at the University of Alabama at Birmingham, with a clinical trials unit well experienced in conducting these studies. There is a strong likelihood of moving our studies from the bench to the clinic. Our military personnel are exposed to solar radiation and extremes of temperature and humidity, all of these contribute to the high prevalence of skin diseases. As a result, skin cancer has been increasing in the military personnel at an astonishing rate over the past several decades, and it is crucial to provide suitable and timely interventions to prevent fatalities. TAK-242 can be a potential agent that can be used for prevention of skin cancer in these individuals along with the sunscreen. The findings from our study will pave the way for clinical trials for management of skin cancer in military personnel. Our studies will represent the next stage in the development of more effective medical interventions for management of non-melanoma skin cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810214
Entities
People
- Nabiha Yusuf
Organizations
- United States Army
- University of Alabama at Birmingham