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.

抽象的 项目3（Curiel）TLR4和TOPK的转化研究和临床药理学 信号路径抑制剂预防鳞状细胞癌 皮肤 三分之三的新癌症中有一个是皮肤癌，使皮肤癌成为全球最常见的恶性肿瘤。 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％。 CSCC的发生率预计 随着人口年龄和防晒保护的行为障碍，继续增加。因此，那里 对社会对与NMSC相关的发病率和医疗保健成本的越来越大的影响 （每年为81亿美元）和精神分裂症（AK）（AK）（肿瘤性CSCC病变；> 10亿/年）。总体目标 该项目是确定Toll样受体4（TLR4）和T-LAK细胞产生的蛋白的临床相关性 激酶（TOPK） / p53相关蛋白激酶（PRPK）信号通路紫外线诱导的人皮 致癌过程导致CSCC发展。此外，我们建议发展有效 这些途径的药理学小分子抑制剂，以建立个性化医学方法 需要在预防环境中进行更有效干预的人群。该项目的假设 是TOPK/ PRPK和TLR4驱动UV诱导的致癌信号通路不人道皮肤，这可以是 药理学针对有效局部预防皮肤CSCC的针对性。我们验证 在慢性紫外线暴露的人类皮肤中，项目1和2中提出的令人鼓舞的临床前结果包括 在我们稳健的档案和预期收集中，评估这些途径的激活状态 临床注释的匹配的人类样本，从日晒受保护的皮肤（SP），阳光受损（SD），AK到 CSCC（AIM 1）。 TLR4和TOPK/PRPK的网络架构将通过 免疫组织化学和反相蛋白微阵列（RPPA）分析用于改变 蛋白/磷蛋白表达和使用纳米串Geomx DSP平台用于空间RNA分析 转录组变化。最终，我们设想确定可以使我们准确的生物标志物的子集 选择将使用一个小分子中的靶向干预措施中受益的患者队列 在此应用中提出的抑制剂。为了评估人皮肤中提出的抑制剂的调节作用， 我们正在使用标准化的急性太阳能模拟光（SSL）模型（AIM 2）。作为这项努力的一部分，我们将 评估使用SD皮肤急性SSL暴露对感兴趣途径的影响（AIM 2A）。随后， 小分子抑制剂将被引入急性人类SSL模型，以确定直接靶向效应 （AIM 2B）。我们的最终目标将评估拟议的TLR4或TOPK/PRPK小的安全性和拟态动力学 分子抑制剂在第一阶段研究中（AIM 3）。该多学科翻译建议着重于新颖 鉴定互补的细胞信号网络及其与其他已建立途径的关系 在皮肤致癌作用中，指导靶向局部小分子的选择和早期临床发展 抑制剂。这将促进一种基于个性化的CSCC治疗方法的方法。