Project 3: Translational Studies and Clinical Pharmacology of TLR4 and TOPK Inhibitors for Prevention of Squamous Cell Carcinoma of the Skin

摘要 项目3(Curiel)TLR4和TOPK的翻译研究和临床药理学 信号通路抑制物预防鳞状细胞癌的研究 皮肤 每三种新癌症中就有一种是皮肤癌，使皮肤癌成为全球最常见的恶性肿瘤。 美国每年约有500万例非黑色素瘤皮肤癌(NMSC)病例。皮肤 鳞状细胞癌(CSCC)占所有NMSC的20-25%。CSCC的发病率预计将 随着人口老龄化和防晒行为障碍的持续存在，这一比例继续增加。因此，在那里 与NMSC相关的发病率和医疗费用对社会的影响是否越来越大？ (81亿美元/年)和光化性角化病(AK)(癌前病变；&gt；10亿/年)。的总目标是 本项目旨在确定Toll样受体4(TLR4)和T-LAK细胞起源蛋白的临床相关性 紫外线照射人皮肤中的TOPK/PRPK信号通路 癌变过程导致宫颈鳞癌的发生。此外，我们建议开发有效的 药理小分子抑制剂的这些途径建立了个性化的药物治疗方法 这一人群需要在预防环境中进行更有效的干预。这个项目的假设是 是TOPK/PRPK和TLR4驱动紫外线诱导的致癌信号通路人类皮肤，这可以是 药理靶向，有效的局部预防皮肤CSCC。我们的方法来验证 项目1和项目2在长期暴露在紫外线下的人体皮肤中展示了令人鼓舞的临床前结果，包括 在我们强大的档案和预期的集合中评估这些通路的激活状态 临床注释的匹配人体样本范围从防晒皮肤(SP)、日光损伤(SD)、AK到 CSCC(目标1)。将通过以下方式评估TLR4和TOPK/PRPK的网络架构 免疫组织化学和反相蛋白芯片(RPPA)分析血管内皮细胞 利用NanoStringGeoMx DSP平台进行蛋白质/磷蛋白表达和空间RNA分析 转录改变。最终，我们设想识别生物标记物的子集，使我们能够准确地 选择将从使用其中一种小分子的靶向干预中受益的患者队列 本申请中提出的抑制剂。为了评估所建议的抑制剂在人体皮肤中的调节作用， 我们正在使用一个标准化的急性太阳模拟光(SSL)模型(目标2)。作为这一努力的一部分，我们将 使用SD皮肤评估急性SSL暴露对感兴趣通路的影响(目标2a)。后来， 小分子抑制剂将被引入急性人类SSL模型以确定直接的靶向效应 (目标2b)。我们的最终目标将评估拟议的TLR4或TOPK/PRPK Small的安全性和药效学 第一阶段研究中的分子抑制剂(目标3)。这项多学科的翻译建议侧重于小说 互补细胞信号网络的识别及其与已建立的其他通路的关系 在皮肤癌发生中，指导靶向局部小分子的选择和早期临床开发 抑制剂。这将促进以个性化为基础的治疗预防CSCC的方法。

ABSTRACT Project 3 (Curiel) Translational Studies and Clinical Pharmacology of TLR4 and TOPK SignalingPathway Inhibitors for Prevention of Squamous Cell Carcinoma of the Skin One out of three new cancers is a skin cancer, making skin cancer the most common malignancy worldwide. Approximately 5 million cases of non-melanoma skin cancer (NMSC) occur annually in the US. Cutaneous squamous cell carcinoma (cSCC) represents 20-25% of all NMSC. The incidence of cSCC is expected to continue to increase as the population ages and behavioral barriers to sun protection persist. Therefore, there is an increasing and substantial impact to society on morbidity and health care costs associated with NMSC ($8.1 billion/year) and actinic keratoses (AK) (preneoplastic cSCC lesions; > 1 billion/year). The overall goal of this project is to determine the clinical relevance of Toll-like Receptor 4 (TLR4) and T-LAK cell-originated protein kinase (TOPK) / p53-related protein kinase (PRPK) signaling pathways in ultraviolet lightinduced human skin carcinogenesis process leading to cSCC development. Furthermore, we propose to develop effective pharmacological small molecule inhibitors of these pathways to establish a personalized medicine approach to this population in need of more effective intervention in the prevention setting. The hypothesis for this project is that TOPK/ PRPK and TLR4 drive UV-induced carcinogenic signaling pathways inhuman skin, which can be pharmacologically targeted for effective topical prevention of cutaneous cSCC. Our approach to validate the encouraging preclinical results presented in projects 1 and 2 in chronically UV exposed human skin includes the assessment of the activation state of these pathways in our robust archive and prospective collection of clinically annotated matched human samples ranging from sun protected skin (SP), sun damaged (SD), AK, to cSCC (Aim 1). The network architecture for TLR4 and TOPK/PRPK will be assessed through immunohistochemistry and reverse phase protein microarray (RPPA) analysis for alterations in protein/phosphoprotein expression, and spatial RNA analysis using the Nanostring GeoMx DSP platform for transcriptomic changes. Ultimately,we envision to identify a subset of biomarkers that can allow us to accurately select the cohort of patients that will benefit from a targeted intervention using one of the small molecule inhibitors proposed in thisapplication. To assess the modulatory effect of the proposed inhibitors in human skin, we are using a standardized acute solar simulated light (SSL) model (Aim 2). As part of this effort we will be evaluating the effect of acute SSL exposure on the pathways of interest using SD skin (Aim 2a). Subsequently, small molecule inhibitors will be introduced to the acute human SSL model to determine direct targeted effects (Aim 2b). Our final aim will assess safety and phamacodynamics of the proposed TLR4 or TOPK/PRPK small molecule inhibitors in a Phase 1 study (Aim 3).This multidisciplinary translational proposal focuses on the novel identification of complementary cellular signaling network and their relationship with other established pathways in skin carcinogenesis, to guide the selection and early clinical development of targeted topical small molecule inhibitors. This will facilitate a personalized based approach for the therapeutic prevention of cSCC.