TASK ORDER: TOPICAL RESATORVID FOR NONMELANOMA SKIN CANCER PREVENTIONPERIOD OF PERFORMANCE: 09/21/2020 - 03/20/2022

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 - 2022 年 3 月 20 日

• 批准号: 10269127
• 负责人: DAVID MCCORMICK
• 金额: $ 21.32万
• 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 2022-03-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10269127
• 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; Preventive Intervention; Quantitative Structure-Activity Relationship; Rattus; Recurrence; Safety; Signal Transduction; Skin; Skin Carcinogenesis; Skin Carcinoma; Stress; TLR4 gene; Topical application; Toxic effect; Toxicology; Translations; Transplant Recipients; UV Radiation Exposure; UV carcinogenesis; UV induced; Ultraviolet B Radiation; Ultraviolet Rays; United States; chemical carcinogenesis; drug candidate; high risk; in silico; in vitro Model; in vivo; keratinocyte; novel; response; skin squamous cell carcinoma; small molecule inhibitor; 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一个主要原因，因为器官移植受者中皮肤鳞状细胞癌 (cSCC) 的发病率是普通人群的 65 至 100 倍。光化性角化病（AK，cSCC 的发育不良前兆）和 cSCC 患者可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 的复发率为 35-80%，这意味着非常需要额外的持续缓解策略。开发具有良好安全性的干预措施非常重要，因为预防性干预预计需要长期和/或重复、间歇性接触候选药物。 皮肤暴露于太阳紫外线 (UV) 辐射是皮肤癌发生的一个致病因素，而炎症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) 已被证明是皮肤炎症失调和化学致癌的主要驱动因素，因为它控制着皮肤光癌发生的多种途径。使用 resatorvid（TAK-242，一种特异性共价 TLR4 小分子抑制剂）对 TLR4 进行药理学抑制已被证明可以在培养的角质形成细胞和紫外线诱导的肿瘤发生的体内动物模型中抑制紫外线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，可导致肿瘤发展减少 60-90%，且几乎没有或没有明显毒性。这些研究表明，在高风险阳光损伤区域使用 resatorvid 局部制剂抑制 TLR4 有可能产生一种新颖、安全且有效的预防 NMSC 的转化策略。 该任务令 RFP 的主要目标是进行体外和体内 IND 毒理学研究，以促进 resatorvid 转化为人体临床试验。