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
基本信息
- 批准号:10410014
- 负责人:
- 金额:$ 23.45万
- 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
- 来源:
- 关键词:Actinic keratosisAcuteAdultAgeArchivesBehavioralBiological AvailabilityBiological MarkersBromidesCancer EtiologyCharacteristicsChemopreventionChronicClinicalClinical PharmacologyCollaborationsCollectionCutaneousDevelopmentDrug TargetingDysplasiaExposure toFormulationFunding MechanismsGeneral PopulationGoalsHealth Care CostsHumanHuman VolunteersImmunohistochemistryIncidenceInterventionKRP proteinLeadLesionLightLinkLymphokine-Activated Killer CellsMalignant NeoplasmsModelingMorbidity - disease rateMusPathway interactionsPatientsPharmaceutical PreparationsPharmacodynamicsPharmacologyPhasePhosphoproteinsPhototherapyPopulationPrevalencePreventionPreventivePreventive MedicineProcessProtein Activation PathwayProtein Array AnalysisProtein KinaseProtein Microarray AssayProtein MicrochipsProteinsRNA analysisSafetySamplingSignal PathwaySignal TransductionSkinSkin CancerSkin CarcinogenesisSkin CarcinomaSocietiesStandardizationStressSun ExposureTLR4 geneTP53 geneTestingThe SunTherapeuticTopical agentTopical applicationUV Radiation ExposureUV inducedUltraviolet Raysaging populationbasecancer chemopreventioncarcinogenesiscarcinogenicityclinical developmentclinical efficacyclinically relevantcohorteffective interventionefficacious interventionexposed human populationinhibitorinterestkeratinocytelaser capture microdissectionmortalitymultidisciplinarynano-stringnetwork architecturenovelnovel therapeuticspatient populationpersonalized medicinephase 1 studyphase 2 studyphase I trialpre-clinicalpreventive interventionprospectiveprotein expressionprotein kinase inhibitorresponseskin cancer preventionskin damageskin squamous cell carcinomasmall moleculesmall molecule inhibitorsun damagesun protectiontranscriptomicstranslational studyultraviolet
项目摘要
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.
摘要
项目3(Curiel)TLR4和TOPK的翻译研究和临床药理学
信号通路抑制物预防鳞状细胞癌的研究
皮肤
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;>;10亿/年)。的总目标是
本项目旨在确定Toll样受体4(TLR4)和T-LAK细胞起源蛋白的临床相关性
紫外线照射人皮肤中的TOPK/PRPK信号通路
癌变过程导致宫颈鳞癌的发生。此外,我们建议开发有效的
药理小分子抑制剂的这些途径建立了个性化的药物治疗方法
这一人群需要在预防环境中进行更有效的干预。这个项目的假设是
是TOPK/PRPK和TLR4驱动紫外线诱导的致癌信号通路人类皮肤,这可以是
药理靶向,有效的局部预防皮肤CSCC。我们的方法来验证
项目1和项目2在长期暴露在紫外线下的人体皮肤中展示了令人鼓舞的临床前结果,包括
在我们强大的档案和预期的集合中评估这些通路的激活状态
临床注释的匹配人体样本范围从防晒皮肤(SP)、日光损伤(SD)、AK到
CSCC(目标1)。将通过以下方式评估TLR4和TOPK/PRPK的网络架构
免疫组织化学和反相蛋白芯片(RPPA)分析血管内皮细胞
利用NanoStringGeoMx DSP平台进行蛋白质/磷蛋白表达和空间RNA分析
转录改变。最终,我们设想识别生物标记物的子集,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队列
本申请中提出的抑制剂。为了评估所建议的抑制剂在人体皮肤中的调节作用,
我们正在使用一个标准化的急性太阳模拟光(SSL)模型(目标2)。作为这一努力的一部分,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)。后来,
小分子抑制剂将被引入急性人类SSL模型以确定直接的靶向效应
(目标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小说
互补细胞信号网络的识别及其与已建立的其他通路的关系
在皮肤癌发生中,指导靶向局部小分子的选择和早期临床开发
抑制剂。这将促进以个性化为基础的治疗预防CSCC的方法。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Clara Curiel-Lewandrowski其他文献
Clara Curiel-Lewandrowski的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Clara Curiel-Lewandrowski', 18)}}的其他基金
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:
$ 23.45万 - 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:
10252871 - 财政年份:2019
- 资助金额:
$ 23.45万 - 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:
$ 23.45万 - 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:
$ 23.45万 - 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:
$ 23.45万 - 项目类别:
相似海外基金
Un/kindness, shame & resistance: the care of inpatients in NHS adult acute mental health units and how it might be improved
Un/善良,羞耻
- 批准号:
2885806 - 财政年份:2023
- 资助金额:
$ 23.45万 - 项目类别:
Studentship
Post-Acute Care Transitions for Older Adult Medicare Beneficiaries with Serious Mental Illness
患有严重精神疾病的老年医疗保险受益人的急性后护理过渡
- 批准号:
10772386 - 财政年份:2023
- 资助金额:
$ 23.45万 - 项目类别:
Paving The Way to a Canadian Standard of Care with CAR-T Cellular Therapy: Phase II Trial of CD19 CAR-T for Relapsed/Refractory Adult Acute Lymphoblastic Leukemia (CLIC-01A)
通过 CAR-T 细胞疗法为加拿大护理标准铺平道路:CD19 CAR-T 治疗复发/难治性成人急性淋巴细胞白血病的 II 期试验 (CLIC-01A)
- 批准号:
474619 - 财政年份:2022
- 资助金额:
$ 23.45万 - 项目类别:
Operating Grants
Investigating the impact acute inhalation of cannabis with a high content of delta-9-tetrahydrocannabinol has on myelination and microglia in adult and aged mice
研究急性吸入高含量 delta-9-四氢大麻酚的大麻对成年和老年小鼠髓鞘形成和小胶质细胞的影响
- 批准号:
485965 - 财政年份:2022
- 资助金额:
$ 23.45万 - 项目类别:
Studentship Programs
Paving The Way to a Canadian Standard of Care with CAR-T Cellular Therapy: Phase II Trial of CD19 CAR-T for Relapsed/Refractory Adult Acute Lymphoblastic Leukemia (CLIC-01A)
通过 CAR-T 细胞疗法为加拿大护理标准铺平道路:CD19 CAR-T 治疗复发/难治性成人急性淋巴细胞白血病的 II 期试验 (CLIC-01A)
- 批准号:
466358 - 财政年份:2022
- 资助金额:
$ 23.45万 - 项目类别:
Operating Grants
Metabolomics for prediction of cisplatin mediated acute kidney injury: a Canadian multi-centre adult and pediatric study
预测顺铂介导的急性肾损伤的代谢组学:加拿大多中心成人和儿童研究
- 批准号:
402040 - 财政年份:2019
- 资助金额:
$ 23.45万 - 项目类别:
Operating Grants
Study of pathogenic mechanism of age-dependent chromosome translocation in adult acute lymphoblastic leukemia
成人急性淋巴细胞白血病年龄依赖性染色体易位发病机制研究
- 批准号:
18K16103 - 财政年份:2018
- 资助金额:
$ 23.45万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Causal effect of time-varying driving pressures on mortality in mechanically ventilated, adult patients with acute respiratory distress syndrome
时变驱动压力对机械通气成年急性呼吸窘迫综合征患者死亡率的因果影响
- 批准号:
377313 - 财政年份:2017
- 资助金额:
$ 23.45万 - 项目类别:
Studentship Programs
Role of SETBP1 in adult Ph+ acute lymphoblastic leukemia
SETBP1 在成人 Ph 急性淋巴细胞白血病中的作用
- 批准号:
9315111 - 财政年份:2016
- 资助金额:
$ 23.45万 - 项目类别:
Acute Inhibition of Adult-born Granule Cells and its Effect on Antidepressant Act
成体颗粒细胞的急性抑制及其抗抑郁作用
- 批准号:
8734273 - 财政年份:2013
- 资助金额:
$ 23.45万 - 项目类别: