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

任务顺序：用于预防非黑色素瘤皮肤癌的局部 RESATORVID 执行期限：2020 年 9 月 21 日 - 2023 年 3 月 31 日

• 批准号: 10551020
• 负责人: DAVID MCCORMICK
• 金额: $ 15.66万
• 依托单位: IIT RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2022-07-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10551020
• 关键词: Actinic keratosis; Acute; Animal Model; Area; Canis familiaris; Cells; Chemopreventive Agent; Chronic; Clinical Trials; Cutaneous; Development; Exposure to; Formulation; Gene Mutation; General Population; Hepatocyte; Human; Immunocompetent; Immunocompromised Host; In Vitro; Incidence; Inflammatory; Intervention; Lead; Macaca; Malignant Neoplasms; Mammalian Cell; Metabolism; Miniature Swine; Morbidity - disease rate; Mus; Organ Transplantation; Pathway interactions; Patients; Performance; Pharmacology; Prevention strategy; Quantitative Structure-Activity Relationship; Rattus; Recurrence; Safety; Signal Transduction; Skin; Skin Carcinogenesis; Skin Carcinoma; Stress; TLR4 gene; Topical application; Toxic effect; Toxicology; Translations; UV Radiation Exposure; UV carcinogenesis; UV induced; Ultraviolet B Radiation; United States; chemical carcinogenesis; drug candidate; high risk; in silico; in vitro Model; in vivo; keratinocyte; novel; organ transplant recipient; preventive intervention; response; skin squamous cell carcinoma; small molecule inhibitor; solar ultraviolet radiation; sun damage; translational approach; tumor; tumorigenesis

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.

非黑色素瘤皮肤癌（NMSC）是美国最常见的恶性肿瘤。NMSC也是器官移植后发病的主要原因，因为皮肤鳞状细胞癌（cSCC）在器官移植受者中的发病率是一般人群的65至100倍。患有光化性角化病（AK，cSCC的发育异常前体）和cSCC的患者采用一系列潜在的化学预防方法进行治疗。然而，治疗后3年AK的复发率范围为35-80%，这意味着非常需要其他持续缓解策略。重要的是开发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/或重复、间歇性暴露于候选药物。 皮肤暴露于太阳紫外线（UV）辐射是皮肤致癌的致病因素，并且炎症失调是急性和慢性UV暴露的有害影响的关键机制。Toll样受体4（TLR 4）已被证明是皮肤炎症失调和化学致癌作用的主要驱动因素，因为它控制着皮肤光致癌作用中涉及的多种途径。已证明使用resatorvid（TAK-242，一种特异性共价TLR 4小分子抑制剂）对TLR 4进行药理学抑制可抑制培养的角质形成细胞和UV诱导肿瘤发生的体内动物模型中UV诱导的应激信号传导和光致癌作用。将Tak-242局部应用于暴露于UVB辐射的免疫功能低下和免疫功能正常的小鼠，导致肿瘤发展减少60-90%，几乎没有或没有明显的毒性。这些研究表明，在高风险的太阳损伤区域使用局部制剂resatorvid抑制TLR 4有可能导致一种新的，安全的，有效的预防NMSC的翻译策略。 本任务指令RFP的主要目的是进行体外和体内IND毒理学研究，以促进将resatorvid转化为人体临床试验。