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

基本信息

  • 批准号:
    10252871
  • 负责人:
  • 金额:
    $ 22.78万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Clara Curiel-Lewandrowski其他文献

Clara Curiel-Lewandrowski的其他文献

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{{ truncateString('Clara Curiel-Lewandrowski', 18)}}的其他基金

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
  • 财政年份:
    2019
  • 资助金额:
    $ 22.78万
  • 项目类别:
Core A: Administration
核心A:管理
  • 批准号:
    10686374
  • 财政年份:
    2019
  • 资助金额:
    $ 22.78万
  • 项目类别:
Targeted Prevention for Non-Melanoma Skin Cancer
非黑色素瘤皮肤癌的针对性预防
  • 批准号:
    10015212
  • 财政年份:
    2019
  • 资助金额:
    $ 22.78万
  • 项目类别:
Core A: Administration
核心A:管理
  • 批准号:
    10268445
  • 财政年份:
    2019
  • 资助金额:
    $ 22.78万
  • 项目类别:
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
  • 财政年份:
    2019
  • 资助金额:
    $ 22.78万
  • 项目类别:
Targeted Prevention for Non-Melanoma Skin Cancer
非黑色素瘤皮肤癌的针对性预防
  • 批准号:
    10410013
  • 财政年份:
    2019
  • 资助金额:
    $ 22.78万
  • 项目类别:
Core A: Administration
核心A:管理
  • 批准号:
    10493964
  • 财政年份:
    2019
  • 资助金额:
    $ 22.78万
  • 项目类别:
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:
    10015218
  • 财政年份:
    2019
  • 资助金额:
    $ 22.78万
  • 项目类别:
Core A: Administration
核心A:管理
  • 批准号:
    10015219
  • 财政年份:
    2019
  • 资助金额:
    $ 22.78万
  • 项目类别:
Core A: Administration
核心A:管理
  • 批准号:
    10475149
  • 财政年份:
    2019
  • 资助金额:
    $ 22.78万
  • 项目类别:

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