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

项目3：TLR4和TOPK抑制剂预防皮肤鳞状细胞癌的转化研究和临床药理学

• 批准号: 10410014
• 负责人: Clara Curiel-Lewandrowski
• 金额: $ 23.45万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410014
• 关键词: Actinic keratosis; Acute; Adult; Age; Archives; Behavioral; Biological Availability; Biological Markers; Bromides; Cancer Etiology; Characteristics; Chemoprevention; Chronic; Clinical; Clinical Pharmacology; Collaborations; Collection; Cutaneous; Development; Drug Targeting; Dysplasia; Exposure to; Formulation; Funding Mechanisms; General Population; Goals; Health Care Costs; Human; Human Volunteers; Immunohistochemistry; Incidence; Intervention; KRP protein; Lead; Lesion; Light; Link; Lymphokine-Activated Killer Cells; Malignant Neoplasms; Modeling; Morbidity - disease rate; Mus; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phosphoproteins; Phototherapy; Population; Prevalence; Prevention; Preventive; Preventive Medicine; Process; Protein Activation Pathway; Protein Array Analysis; Protein Kinase; Protein Microarray Assay; Protein Microchips; Proteins; RNA analysis; Safety; Sampling; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Societies; Standardization; Stress; Sun Exposure; TLR4 gene; TP53 gene; Testing; The Sun; Therapeutic; Topical agent; Topical application; UV Radiation Exposure; UV induced; Ultraviolet Rays; aging population; base; cancer chemoprevention; carcinogenesis; carcinogenicity; clinical development; clinical efficacy; clinically relevant; cohort; effective intervention; efficacious intervention; exposed human population; inhibitor; interest; keratinocyte; laser capture microdissection; mortality; multidisciplinary; nano-string; network architecture; novel; novel therapeutics; patient population; personalized medicine; phase 1 study; phase 2 study; phase I trial; pre-clinical; preventive intervention; prospective; protein expression; protein kinase inhibitor; response; skin cancer prevention; skin damage; skin squamous cell carcinoma; small molecule; small molecule inhibitor; sun damage; sun protection; transcriptomics; translational study; ultraviolet

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.

摘要 项目3（Curiel）TLR 4和TOPK的转化研究和临床药理学 信号通路抑制剂预防乳腺癌的研究进展 皮肤 三分之一的新癌症是皮肤癌，使皮肤癌成为世界上最常见的恶性肿瘤。 在美国，每年发生约500万例非黑色素瘤皮肤癌（NMSC）。皮肤 鳞状细胞癌（cSCC）占所有NMSC的20-25%。预计cSCC的发病率 随着人口老龄化和防晒行为障碍的持续存在，因此 对NMSC相关的发病率和医疗保健费用的社会影响越来越大 （$81亿/年）和光化性角化病（AK）（癌前cSCC病变; > 10亿/年）。的总目标 该项目旨在确定Toll样受体4（TLR 4）和T-LAK细胞源蛋白的临床相关性 紫外线诱导人皮肤中TOPK/PRPK信号通路的研究 导致cSCC发展的致癌过程。此外，我们建议发展有效的 这些途径的药理学小分子抑制剂，以建立个性化的医学方法， 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 TOPK/ PRPK和TLR 4驱动紫外线诱导的致癌信号通路， 针对皮肤cSCC的有效局部预防。我们验证 在项目1和2中，在长期暴露于紫外线的人类皮肤中呈现了令人鼓舞的临床前结果，包括 在我们强大的档案和前瞻性收集的这些途径的激活状态的评估， 临床上注释的匹配的人类样品，范围从防晒皮肤（SP）、晒伤（SD）、AK，到 cSCC（目标1）。TLR 4和TOPK/PRPK的网络架构将通过 免疫组织化学和反相蛋白质微阵列（RPPA）分析， 蛋白质/磷蛋白表达，并使用Nanostring GeoMx DSP平台进行空间RNA分析， 转录组学变化。最终，我们设想确定一个生物标志物的子集，可以让我们准确地 选择将受益于使用小分子之一的靶向干预的患者队列 本申请中提出的抑制剂。为了评估所提出的抑制剂在人皮肤中的调节作用， 我们正在使用标准化的急性太阳模拟光（SSL）模型（目标2）。作为这项工作的一部分，我们将 使用SD皮肤评价急性SSL暴露对感兴趣的途径的影响（目标2a）。随后，委员会注意到， 将小分子抑制剂引入急性人SSL模型以确定直接靶向效应 (Aim 2b）。我们的最终目的是评估所提出的TLR 4或TOPK/PRPK小分子的安全性和药效学。 分子抑制剂的1期研究（目标3）。这个多学科的翻译建议的重点是新的 互补细胞信号网络的鉴定及其与其他已建立的通路的关系 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 抑制剂的这将促进基于个性化的方法用于治疗性预防cSCC。