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 用于预防鳞状细胞癌的信号通路抑制剂 皮肤 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）。总体目标为 该项目旨在确定 Toll 样受体 4 (TLR4) 和 T-LAK 细胞来源蛋白的临床相关性 紫外线诱导的人体皮肤中激酶 (TOPK) / p53 相关蛋白激酶 (PRPK) 信号通路 导致 cSCC 发展的致癌过程。此外，我们建议制定有效的 这些途径的药理学小分子抑制剂，以建立个性化医疗方法 这些人群需要在预防环境中进行更有效的干预。本项目的假设 TOPK/ PRPK 和 TLR4 驱动人类皮肤中紫外线诱导的致癌信号通路，这可以 药物靶向有效局部预防皮肤鳞状细胞癌。我们验证的方法 项目 1 和 2 中在长期暴露于紫外线的人体皮肤中取得的令人鼓舞的临床前结果包括 在我们强大的档案和前瞻性收集中评估这些途径的激活状态 临床注释的匹配人体样本，范围从防晒皮肤 (SP)、晒伤皮肤 (SD)、AK 到 cSCC（目标 1）。 TLR4 和 TOPK/PRPK 的网络架构将通过以下方式进行评估 免疫组织化学和反相蛋白微阵列（RPPA）分析改变 使用 Nanostring GeoMx DSP 平台进行蛋白质/磷蛋白表达和空间 RNA 分析 转录组变化。最终，我们希望识别出生物标志物的子集，使我们能够准确地 选择将从使用其中一种小分子的靶向干预中受益的患者群体 本申请中提出的抑制剂。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的急性太阳模拟光 (SSL) 模型（目标 2）。作为这项努力的一部分，我们将 使用 SD 皮肤评估急性 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效果 （目标 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新颖的 互补细胞信号网络的识别及其与其他已建立途径的关系 在皮肤癌发生过程中，指导靶向外用小分子的选择和早期临床开发 抑制剂。这将促进基于个性化的 cSCC 治疗预防方法。