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

项目3：TLR4和TOPK信号通路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: 10475143
• 负责人: Clara Curiel-Lewandrowski
• 金额: $ 22.42万
• 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/10475143
• 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; Individual; 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; Risk; 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; network architecture; novel; novel therapeutics; patient population; personalized medicine; phase 1 study; phase 2 study; phase I trial; pre-clinical; preventive intervention; prospective; protein kinase inhibitor; response; skin cancer prevention; skin damage; skin squamous cell carcinoma; small molecule; small molecule inhibitor; sun damage; sun protection; translational study

ABSTRACT Project 3 (Curiel,Chow) Translational Studies and Clinical Pharmacology of TLR4 and TOPK Signaling Pathway 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 light induced human skin carcinogenesis process leading to cSCC development. Furthermore, we propose to develop effective pharmacological small molecule inhibitors of these pathways to etsablish 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 in human 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 protein/phosphoprotein network architecture for TLR4 and TOPK/PRPK will be assessed through IHC and reverse phase protein microarray (RPPA) analysis. Ultimately we envision to identfy a subset of biomarkers by IHC 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 this application. To asses 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). Susbsequently, 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，Chow）TLR4和TOPK信号的转化研究和临床药理学 预防皮肤鳞状细胞癌的途径抑制剂 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）。 该项目的总体目标是确定类似收费受体4（TLR4）和T-LAK的临床相关性 在紫外线中，与细胞原始的蛋白激酶（TOPK） / p53相关蛋白激酶（PRPK）信号通路 诱导人类皮肤致癌过程，导致CSCC发育。此外，我们建议 开发这些途径的有效的药理学小分子抑制剂，以使一个个性化 在预防环境中需要更有效干预的该人群的医学方法。这 该项目的假设是TOPK/ PRPK和TLR4驱动紫外线诱导的致癌信号通路 人体皮肤，可以在药理学上针对有效局部预防皮肤CSCC。我们的 验证项目1和2中提出的令人鼓舞的临床前结果的方法 暴露的人皮包括在我们稳健的档案中评估这些途径的激活状态 并预期收集临床注释的匹配的人类样品，这些样品从受保护的皮肤不等 （SP），损坏的太阳（SD），AK，到CSCC（AIM 1）。 TLR4和 TOPK/PRPK将通过IHC和反相蛋白微阵列（RPPA）分析进行评估。最终 我们设想识别IHC的生物标志物的子集，以使我们能够准确选择同类 使用靶向干预措施受益的患者使用其中提出的一种小分子抑制剂 应用。为了评估人类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（SSL）模型（AIM 2）。作为这项努力的一部分，我们将评估 急性SSL暴露对使用SD皮肤感兴趣的途径的影响（AIM 2A）。 SUSB，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 1期研究中的分子抑制剂（AIM 3）。 这个多学科的翻译建议着重于补充细胞的新颖识别 信号网络及其与皮肤致癌中其他既定途径的关系，以指导 靶向局部小分子抑制剂的选择和早期临床发展。这将有助于 基于个性化的CSCC治疗预防方法。