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.

抽象的 项目 3 (Curiel,Chow) TLR4 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，这使得皮肤癌成为全世界最常见的恶性肿瘤。 美国每年约有 500 万例非黑色素瘤皮肤癌 (NMSC)。皮肤的 鳞状细胞癌 (cSCC) 占所有 NMSC 的 20-25%。 cSCC 的发病率预计 随着人口老龄化和防晒行为障碍的持续存在，这种情况继续增加。因此，有 与 NMSC 相关的发病率和医疗保健费用对社会产生越来越大的重大影响 （81 亿美元/年）和光化性角化病 (AK)（癌前 cSCC 病变；> 10 亿/年）。 该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 紫外光下细胞源性蛋白激酶 (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，以建立个性化治疗 对需要在预防环境中进行更有效干预的人群采取医学方法。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 人类皮肤，可以在药理学上靶向有效局部预防皮肤鳞状细胞癌。我们的 验证项目 1 和 2 在长期紫外线方面令人鼓舞的临床前结果的方法 暴露的人体皮肤包括对我们强大档案中这些途径的激活状态的评估 以及前瞻性收集临床注释的匹配人类样本，范围包括防晒皮肤 (SP)、晒伤 (SD)、AK、cSCC（目标 1）。 TLR4 的蛋白质/磷蛋白网络架构 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 IHC 识别生物标志物的子集，这可以让我们准确地选择队列 将从使用本文中提出的小分子抑制剂之一进行有针对性的干预中受益的患者 应用。为了评估所提出的抑制剂对人体皮肤的调节作用，我们正在使用 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 使用 SD 皮肤急性 SSL 暴露对感兴趣通路的影响（目标 2a）。随后，小 分子抑制剂将被引入急性人类 SSL 模型中以确定直接靶向作用（Aim 2b）。我们的最终目标是评估拟议的 TLR4 或 TOPK/PRPK 小药物的安全性和药效学 第一阶段研究（目标 3）中的分子抑制剂。 这项多学科转化提案重点关注互补细胞的新鉴定 信号网络及其与皮肤癌发生中其他已建立途径的关系，以指导 靶向局部小分子抑制剂的选择和早期临床开发。这将有利于 基于个性化的 cSCC 治疗预防方法。