Project 1: TLR4 as a Novel Target for Skin Cancer Prevention

摘要 项目1（Wondrak，Dickinson）TLR 4作为皮肤癌预防的新靶点 非黑色素瘤皮肤癌（NMSC）是全球最常见的恶性肿瘤， 发病率，代表着不断扩大的公共卫生和经济负担。皮肤暴露于日光 紫外线（UV）辐射是皮肤癌发生的主要致病因素， 对于NMSC的有效化学预防是迫切需要的。通过TLR 4（Toll样）的炎症信号传导 受体4）已显示驱动皮肤炎症失调和化学致癌作用。我们自己 数据首次证明药理学TLR 4拮抗作用可以抑制UV诱导的应激， 在培养的角质形成细胞和SKH-1小鼠模型中的信号传导和光致癌作用。使用TLR 4定向 遗传和药理学实验，我们建议测试新的假设，这种受体是一种 皮肤光致癌作用的主要介质和治疗靶点。为此，我们将首先使用转基因 小鼠模型，以检查角化细胞衍生的TLR 4信号传导作为急性UV- 诱导的光损伤、光免疫抑制和光致癌作用。这些模型将比较 野生型小鼠对表皮特异性TLR 4敲除小鼠以及总TLR 4敲除小鼠的应答 SKH-1无毛背景下的小鼠（目标1）。接下来，研究药物调节TLR 4的可行性。 将在急性和慢性紫外线暴露的小鼠模型中测试皮肤癌光化学预防的信号传导 (Aim 2）。我们最近的初步研究结果表明，我们的先导化合物，resatorvid（TAK-242，一种特异性共价键， TLR 4小分子抑制剂）显著抑制SKH-1小鼠中UV诱导的肿瘤发生。因此，急性 Aim 2的长期研究集中在比较resatorvid与其他主要TLR 4通路抑制剂， 以及在测试先导化合物之一的临床相关乳膏制剂的功效时 （由Core D开发）在小鼠上进行，以帮助项目3进行的即将进行的临床试验。 最后，作为一个发展目标，我们将比较临床相关的TLR 4激动剂和 拮抗剂对细胞培养物和SKH-1小鼠皮肤中UV诱导的细胞凋亡和应激信号传导的影响。的 这些研究的临床前和转化结果将告知我们治疗靶向TLR 4的能力， 作为一种手段，防止NMSC在响应人群。

ABSTRACT Project 1 (Wondrak, Dickinson) TLR4 as a Novel Target for Skin Cancer Prevention Nonmelanoma skin cancer (NMSC) is the most common malignancy worldwide and is rapidly increasing in incidence, representing an expanding public health and economic burden. Cutaneous exposure to solar ultraviolet (UV) radiation is a major causative factor in skin carcinogenesis, and improved molecular strategies for efficacious chemoprevention of NMSC are urgently needed. Inflammatory signaling through TLR4 (Toll-like receptor 4) has been shown to drive skin inflammatory dysregulation and chemical carcinogenesis. Our own data demonstrate for the first time that pharmacological TLR4 antagonism can suppress UV-induced stress signaling and photocarcinogenesis in cultured keratinocytes and SKH-1 mouse models. Using TLR4-directed genetic and pharmacological experimentation, we propose to test the novel hypothesis that this receptor is a major mediator and therapeutic target in skin photocarcinogenesis. To this end, we will first use transgenic mouse models to examine the role of keratinocyte-derived TLR4 signaling as a crucial mediator of acute UV- induced photodamage, photoimmunosuppression and photocarcinogenesis. These models will compare the responses of wildtype mice to those of epidermis-specific TLR4 knockout mice as well as total TLR4 knockout mice on the SKH-1 hairless background (Aim 1). Next, the feasibility of pharmacological modulation of TLR4 signaling for skin cancer photochemoprevention will be tested in acute and chronic UV-exposed mouse models (Aim 2). Our recent preliminary findings show that our lead compound, resatorvid (TAK-242, a specific covalent TLR4 small molecule inhibitor) significantly inhibits UV-induced tumorigenesis in SKH-1 mice. Thus, the acute and chronic studies of Aim 2 are focused upon comparing resatorvid to other lead TLR4 pathway inhibitors, as well as upon testing the efficacy of a clinically-relevant cream formulation of one of the lead compounds (developed by Core D) on mice in the interest of aiding forthcoming clinical trials performed by Project 3. Finally, as a developmental aim, we will compare the effects of clinically-relevant TLR4 agonists and antagonists on UV-induced apoptosis and stress signaling in both cell culture and SKH-1 mouse skin. The preclinical and translational results of these studies will inform our ability to therapeutically target the TLR4 pathway as a means of preventing NMSC in responsive populations.