TASK ORDER: TOPICAL RESATORVID FOR NONMELANOMA SKIN CANCER PREVENTIONPERIOD OF PERFORMANCE: 09/21/2020 - 03/31/2023

非黑色素瘤皮肤癌（NMSC）是美国最常见的恶性肿瘤。NMSCs也是器官移植后发病的主要原因，因为在器官移植受者中，皮肤鳞状细胞癌（cSCC）的发病率比一般人群高65至100倍。光化性角化病（AK， cSCCs的一种发育不良前体）和cSCC患者可以使用一系列潜在的化学预防方法进行治疗。然而，治疗后3年的AKs复发率在35-80%之间，这意味着需要额外的持续反应策略。开发具有良好安全性的干预措施是很重要的，因为预防性干预预计需要长期和/或反复、间歇性地暴露于候选药物。

Nonmelanoma skin cancer (NMSC) is the most common malignancy in the United States. NMSCs also represent a major cause of morbidity after organ transplantation as cutaneous squamous cell carcinomas (cSCC) have a 65 to 100-fold greater incidence in organ transplant recipients compared to the general population. Patients with Actinic Keratosis (AK, a dysplastic precursor to cSCCs) and cSCC are treated with a range of potential chemopreventive approaches. However, the recurrence rate of AKs following therapy ranges from 35-80% at 3 years, implying that additional strategies for sustained responses are much needed. It is important to develop interventions with a good safety profile, since preventive intervention is expected to require long term and/or repeated, intermittent exposure to the candidate drugs. Cutaneous exposure to solar ultraviolet (UV) radiation is a causative factor in skin carcinogenesis, and inflammatory dysregulation is a key mechanism underlying the detrimental effects of acute and chronic UV exposure. Toll-like receptor 4 (TLR4) has been shown to be a major driver of skin inflammatory dysregulation and chemical carcinogenesis as it controls multiple pathways involved in skin photocarcinogenesis. Pharmacological inhibition of TLR4 using resatorvid (TAK-242, a specific covalent TLR4 small molecule inhibitor) has been shown to suppress UV-induced stress signaling and photocarcinogenesis in cultured keratinocytes and in vivo animal models of UV induced tumorigenesis. Topical application of Tak-242 to both immunocompromised and immunocompetent mice exposed to UVB radiation resulted in 60-90% decreases in tumor development with little or no apparent toxicity. These studies suggest that inhibition of TLR4 using a topical formulation of resatorvid in high-risk sun-damaged areas has the potential to lead to a novel, safe, and effective translational strategy for prevention of NMSC. The main objectives of this Task Order RFP are to perform in vitro and in vivo IND-enabling toxicology studies to facilitate translation of resatorvid to human clinical trials.