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
- 来源:
- 关键词:Actinic keratosisAcuteAdultAgeArchivesBehavioralBiological AvailabilityBiological MarkersBromidesCancer EtiologyCharacteristicsChemopreventionChronicClinicalClinical PharmacologyCollaborationsCollectionCutaneousDevelopmentDrug TargetingDysplasiaExposure toFormulationFunding MechanismsGeneral PopulationGoalsHealth Care CostsHumanHuman VolunteersImmunohistochemistryIncidenceIndividualInterventionKRP proteinLeadLesionLightLinkLymphokine-Activated Killer CellsMalignant NeoplasmsModelingMorbidity - disease rateMusPathway interactionsPatientsPharmaceutical PreparationsPharmacodynamicsPharmacologyPhasePhosphoproteinsPhototherapyPopulationPrevalencePreventionPreventivePreventive MedicineProcessProtein Activation PathwayProtein Array AnalysisProtein KinaseProtein Microarray AssayProtein MicrochipsProteinsRiskSafetySamplingSignal PathwaySignal TransductionSkinSkin CancerSkin CarcinogenesisSkin CarcinomaSocietiesStandardizationStressSun ExposureTLR4 geneTP53 geneTestingThe SunTherapeuticTopical agentTopical applicationUV Radiation ExposureUV inducedUltraviolet Raysaging populationbasecancer chemopreventioncarcinogenesiscarcinogenicityclinical developmentclinical efficacyclinically relevantcohorteffective interventionefficacious interventionexposed human populationinhibitor/antagonistinterestkeratinocytelaser capture microdissectionmortalitymultidisciplinarynetwork architecturenovelnovel therapeuticspatient populationpersonalized medicinephase 1 studyphase 2 studyphase I trialpre-clinicalpreventive interventionprospectiveprotein kinase inhibitorresponseskin cancer preventionskin damageskin squamous cell carcinomasmall moleculesmall molecule inhibitorsun damagesun protectiontranslational study
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:
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:
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:
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:
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