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

摘要 项目1(Wondrak，Dickinson)TLR4作为皮肤癌预防的新靶点 非黑色素瘤皮肤癌(NMSC)是世界上最常见的恶性肿瘤，在 发病率增加，公共卫生和经济负担不断扩大。皮肤暴露在阳光下 紫外线(UV)辐射是皮肤癌的主要诱因，并改进了分子策略 对于NMSC的有效化学预防是迫切需要的。通过TLR4(Toll样蛋白)传递炎症信号 受体4)已被证明可导致皮肤炎症、失调和化学致癌。我们自己的 首次有数据表明，药物上的TLR4拮抗剂可以抑制紫外线诱导的应激反应 培养的角质形成细胞和SKH-1小鼠模型中的信号与光致癌。使用TLR4定向 通过遗传学和药理学实验，我们建议检验这种受体是一种 皮肤光癌发生的主要介导物和治疗靶点。为此，我们将首先使用转基因 小鼠模型研究角质形成细胞来源的TLR4信号作为急性紫外线的重要介导物的作用 诱导光损伤、光免疫抑制和光致癌。这些模型将比较 野生型小鼠对表皮特异性TLR4基因敲除小鼠和TLR4基因全部敲除小鼠的反应 SKH-1无毛背景上的小鼠(目标1)。接下来，对TLR4进行药理调节的可行性研究 皮肤癌的光化学预防信号将在急性和慢性紫外线照射的小鼠模型中进行测试 (目标2)。我们最近的初步发现表明，我们的先导化合物resatorvid(TAK-242，一种特定的共价 TLR4小分子抑制剂)显著抑制紫外线诱导的SKH-1小鼠肿瘤形成。因此，急性 而对AIM 2的长期研究集中在将resatorvid与其他先导TLR4途径抑制剂AS进行比较 以及测试其中一种先导化合物的临床相关乳膏配方的有效性 (由Core D开发)用于小鼠，以帮助项目3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TLR4激动剂和 紫外线诱导细胞培养和SKH-1小鼠皮肤中的细胞凋亡和应激信号的拮抗剂。这个 这些研究的临床前和翻译结果将为我们提供治疗靶向TLR4的能力 途径作为预防反应人群中NMSC的一种手段。

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.