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: 10252871
• 负责人: Clara Curiel-Lewandrowski
• 金额: $ 22.78万
• 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/10252871
• 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/antagonist; 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.

摘要 项目3（Curiel，Chow）TLR 4和TOPK信号转导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）。 本项目的总体目标是确定Toll样受体4（TLR 4）和T-LAK的临床相关性 紫外光下的细胞源蛋白激酶（TOPK）/ p53相关蛋白激酶（PRPK）信号通路 诱导人类皮肤癌变过程，导致cSCC的发展。此外，我们建议 开发这些途径的有效药理学小分子抑制剂，以建立个性化的 在预防环境中，需要对这一人群采取更有效的干预措施。的 该项目假设是TOPK/ PRPK和TLR 4驱动UV诱导的致癌信号通路， 人皮肤，其可被靶向用于有效局部预防皮肤cSCC。我们 一种方法来验证项目1和2中提出的令人鼓舞的临床前结果， 暴露的人类皮肤包括在我们强大的档案这些途径的激活状态的评估 和前瞻性收集临床注释的匹配人类样本， (SP)日晒损伤（SD），AK，至cSCC（Aim 1）。TLR 4的蛋白质/磷蛋白网络结构， TOPK/PRPK将通过IHC和反相蛋白微阵列（RPPA）分析进行评估。最终 我们设想通过免疫组化鉴定生物标志物的子集，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一种小分子抑制剂的靶向干预， 应用程序.为了评估拟议抑制剂对人类皮肤的调节作用，我们使用了 标准化急性太阳模拟光（SSL）模型（Aim 2）。作为这项工作的一部分，我们将评估 急性SSL暴露对使用SD皮肤的感兴趣途径的影响（目标2a）。小尺寸 将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。 1期研究中的分子抑制剂（目标3）。 这个多学科的翻译建议集中在新的识别互补的细胞 信号网络及其与其他已建立的皮肤癌发生途径的关系，以指导 靶向局部小分子抑制剂的选择和早期临床开发。这将有助于A 基于个性化的方法用于治疗性预防cSCC。