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率的主要原因，因为皮肤鳞状细胞癌(CSCC)在器官移植受者中的发病率是普通人群的65到100倍。光化性角化病(AK，鳞状细胞癌的发育不良先兆)和鳞状细胞癌的患者可以采用一系列潜在的化学预防方法进行治疗。然而，治疗后AKS的复发率在3年内从35-80%不等，这意味着迫切需要更多的持续反应策略。重要的是制定具有良好安全性的干预措施，因为预防性干预预计需要长期和/或反复、间歇性地接触候选药物。 皮肤暴露于太阳紫外线(UV)辐射是导致皮肤癌的一个因素，而炎症调节失调是急性和慢性紫外线暴露有害影响的关键机制。Toll样受体4(TLR4)是皮肤炎性失调和化学致癌的主要驱动力，它控制着参与皮肤光癌发生的多个途径。用白藜芦醇(TAK-242，一种特异性的共价TLR4小分子抑制剂)抑制TLR4的药理作用已被证明在培养的角质形成细胞和体内紫外线诱导的肿瘤动物模型中抑制紫外线诱导的应激信号和光癌。将Tak-242局部应用于暴露在UVB辐射下的免疫低下和免疫正常的小鼠，可使肿瘤发展减少60%-90%，且几乎没有明显的毒性。这些研究表明，在日照受损的高危地区使用局部制剂来抑制TLR4有可能导致一种新的、安全和有效的翻译策略来预防NMSC。 该任务单RFP的主要目标是进行体外和体内IND毒理学研究，以促进将resatorvid转化为人类临床试验。

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.