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: 10686373
• 负责人: Clara Curiel-Lewandrowski
• 金额: $ 22.75万
• 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/10686373
• 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; Phase; Phosphoproteins; Phototherapy; Population; Prevalence; Prevention; Prevention strategy; 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; Testing; Therapeutic; Topical agent; Topical application; UV induced; Ultraviolet Rays; aging population; 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; neoplastic; network architecture; novel; novel therapeutics; p53 related protein kinase; patient population; personalized medicine; pharmacologic; phase 1 study; phase 2 study; phase I trial; pre-clinical; preventive intervention; prospective; protein kinase inhibitor; response; safety assessment; 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.

摘要 TLR4和TOPK信号转译研究及临床药理学研究 预防皮肤鳞状细胞癌的途径抑制物 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)。 本项目的总体目标是确定Toll样受体4(TLR4)和T-LAK的临床相关性 紫外光中细胞起源蛋白激酶(TOPK)/P53相关蛋白激酶(PRPK)信号转导途径 诱导人类皮肤癌的发生过程，导致口腔鳞癌的发生。此外，我们建议 开发这些途径的有效药理小分子抑制剂以实现个性化 医学方法需要在预防环境中对这一人群进行更有效的干预。这个 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，可通过药理学靶向有效地局部预防皮肤鳞状细胞癌。我们的 验证项目1和项目2在慢性紫外线中提出的令人鼓舞的临床前结果的方法 暴露的人类皮肤包括在我们强大的档案中评估这些通路的激活状态 以及预期收集的临床注释匹配的人体样本，范围从防晒皮肤 (SP)，阳光损伤(SD)，AK，到CSCC(目标1)。TLR4和TLR4的蛋白质/磷蛋白网络结构 TOPK/PRPK将通过IHC和反相蛋白质芯片(RPPA)分析进行评估。最终 我们设想通过IHC识别生物标记物的子集，使我们能够准确地选择 患者将受益于使用本研究中提出的小分子抑制剂之一的靶向干预 申请。为了评估建议的抑制剂在人体皮肤中的调节作用，我们使用了一种 标准化急性太阳模拟光(SSL)模型(目标2)。作为这项工作的一部分，我们将评估 急性SSL暴露对SD皮肤感兴趣通路的影响(目标2a)。随之而来的，小的 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 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互补细胞的新鉴定 皮肤癌发生中的信号网络及其与其他已建立的通路的关系，以指导 靶向局部小分子抑制剂的选择和早期临床开发。这将促进 以个性化为基础的口腔鳞癌治疗性预防。