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: 10817653
• 负责人: DAVID MCCORMICK
• 金额: $ 64.46万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10817653
• 关键词: Actinic keratosis; Acute; Animal Model; Area; Canis familiaris; Cells; Chemopreventive Agent; Chronic; Clinical Trials; Cutaneous; Dermal; Development; Dose; Exposure to; Formulation; Gene Mutation; General Population; Hepatocyte; Human; Immunocompetent; Immunocompromised Host; In Vitro; Incidence; Inflammatory; Intervention; Macaca; Malignant Neoplasms; Mammalian Cell; Metabolism; Miniature Swine; Morbidity - disease rate; Mus; Organ Transplantation; Pathway interactions; Patients; Performance; Prevention strategy; Quantitative Structure-Activity Relationship; Rattus; Recurrence; Safety; Signal Transduction; Skin; Skin Carcinogenesis; Skin Carcinoma; Stress; TLR4 gene; Topical application; Toxic effect; Toxicokinetics; 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; pharmacologic; 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还代表了器官移植后发病率的主要原因，因为皮肤鳞状细胞癌（CSCC）与一般人群相比，器官移植受者的发生率更高65至100倍。活化性角化病（AK，CSCC的发育异常前体）和CSCC患者采用一系列潜在的化学预防方法治疗。但是，治疗后AK的复发率在3年的35-80％之间，这意味着急需持续反应的其他策略。重要的是要开发具有良好安全性的干预措施，因为预防预防性干预需要长期和/或重复，间歇性接触候选药物。 皮肤暴露于太阳能紫外线（UV）辐射是皮肤致癌的原因，炎症失调是急性和慢性紫外线暴露的有害作用的关键机制。 Toll样受体4（TLR4）已被证明是皮肤炎症失调和化学癌变的主要驱动因素，因为它控制了与皮肤光钙化相关的多种途径。已经证明，使用ResatorVID（TAK-242，一种特定的共价TLR4小分子抑制剂）对TLR4的药理抑制作用已证明可以抑制培养的角质形成细胞和UV诱导肿瘤发生的Vivo动物模型中紫外线诱导的应激信号传导和光钙齐的发生。 TAK-242的局部应用在暴露于UVB辐射的免疫功能低下和免疫能力的小鼠中导致肿瘤发育的60-90％降低，几乎没有或没有明显的毒性。这些研究表明，使用在高风险的阳光损害区域中局部配方对TLR4的抑制有可能导致一种新型，安全且有效的转化策略，以预防NMSC。 该任务顺序RFP的主要目标是在体外和体内毒理学研究，以促进将重新植物转化为人类临床试验。