Mechanism and Therapeutic Targeting of TRIM29-mediated Invasion in Bladder Cancer
TRIM29介导的膀胱癌侵袭的机制和治疗靶向
基本信息
- 批准号:10500881
- 负责人:
- 金额:$ 43.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-01 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAnimal ModelAreaAutomobile DrivingBindingBiological AssayBiological MarkersBiologyBladder NeoplasmCancer ModelCellsClinicalComplexDNA RepairDevelopmentDiagnosisDiseaseEarly DiagnosisEarly identificationEventFocal AdhesionsGoalsHumanImmuneIntermediate FilamentsKeratinKnowledgeLocal TherapyMalignant neoplasm of urinary bladderMediatingMicroRNAsMissionModelingMolecularMolecular ConformationMolecular TargetMuscleMutationNeoplasm MetastasisOncogenicOutcomePTK2 genePathway interactionsPatient-Focused OutcomesPatientsPersonsPharmaceutical PreparationsPreventionProcessProteinsPublic HealthRegulationRelapseResearchRiskRoleSRC geneSignal TransductionStructureTRIM MotifTestingTherapeuticTherapeutic InterventionTumor Cell InvasionUbiquitinationUnited Statesbeta catenincancer initiationcancer invasivenesshigh riskhuman diseaseimprovedin vivoinhibitorinnate immune pathwaysinnovationinsightinterestlive cell imagingmortalitymouse modelmuscle invasive bladder cancernew therapeutic targetnovelnovel therapeutic interventionpaxillinpreventscaffoldtherapeutic targettherapy resistantthree-dimensional modelingtumortumor initiationtumor progressionubiquitin ligase
项目摘要
Over 17,000 will die from bladder cancer in the U.S. this year. While most patients with noninvasive tumors are
cured, most patients with muscle-invasive disease will develop metastases and die. Therefore, understanding
and targeting the molecular driver(s) which facilitate this invasive switch is essential to improve patient
outcomes. TRIM29 is a critical driver of bladder cancer initiation, invasion and therapeutic resistance in human
tumors and mouse models. TRIM29 promotes tumor formation by regulating protein interactions that govern
beta-catenin and miRNA activity. TRIM29 impacts therapeutic resistance by regulating ubiquitination of DNA
repair and innate immune pathways. The specific mechanism by which TRIM29 drives invasive progression
remains poorly understood. Rationale: Emerging evidence from our lab has identified a novel function of
TRIM29 in the regulation of intermediate filaments, focal adhesion and FAK/Src signaling. However, we do not
yet understand how this TRIM29-focal adhesion axis is regulated, how it participates in progression from non-
invasive to invasive cancers in vivo or how it coordinates with previously identified mechanisms to promote
invasive progression. This is a critical gap in knowledge because without a clear understanding of these
events, we are unable to develop therapeutic strategies to target this pathway and prevent progression to the
lethal invasive form of bladder cancer. The specific objective of this proposal is to identify the role of this novel
TRIM29-focal adhesion axis in invasive progression and to use this knowledge to develop therapeutic
strategies to block invasive progression in high-risk TRIM29+ tumors. The central hypothesis is that TRIM29
drives progression from noninvasive to lethal invasive bladder cancer by driving intermediate filament
and focal adhesion formation, and activation of FAK/Src signaling in invasive cells. This hypothesis will
be tested in the following specific aims: 1) To conduct detailed structure-function analysis of the TRIM29
interaction with intermediate filaments, the focal adhesion complex, and FAK/Src signaling during invasion. 2)
To determine the requirement for TRIM29, KRT14, and focal adhesion proteins during bladder cancer initiation
and invasive progression. 3) To evaluate novel therapeutic strategies to block TRIM29-mediated invasion in
bladder cancer. Aim 1 will utilize live cell imaging, 3D and animal models of invasion. Aim 2 will leverage
unique GEMM of bladder cancer to dissect the essential functions of TRIM29 in vivo. Aim 3 will use our
multiple models to identify therapeutic strategies to target TRIM29-mediated invasion. This research is
conceptually innovative in the characterization of a novel TRIM29-focal adhesion pathway of invasive
progression and technically innovative in the development of novel bladder cancer murine models, advanced
3D tumor invasion assays and novel therapeutic targeting strategies. The proposed research is significant
because description of the mechanism of TRIM29-mediated invasive progression will allow identification of
novel therapeutic strategies to block development of lethal invasive progression in bladder cancer.
今年美国将有超过17,000人死于膀胱癌。虽然大多数非侵袭性肿瘤患者
如果治愈,大多数肌肉侵袭性疾病患者将发生转移并死亡。因此了解
并且靶向促进这种侵入性转换的分子驱动器对于改善患者
成果。TRIM 29是人类膀胱癌发生、侵袭和治疗抗性的关键驱动因素
肿瘤和小鼠模型。TRIM 29通过调节蛋白质相互作用促进肿瘤形成,
β-连环蛋白和miRNA活性。TRIM 29通过调节DNA的泛素化影响治疗抗性
修复和先天免疫途径。TRIM 29驱动侵袭性进展的具体机制
仍然知之甚少。理由:我们实验室的新证据已经确定了一种新的功能,
TRIM 29在调节中间丝、粘着斑和FAK/Src信号中的作用但我们不
然而,了解TRIM 29-粘着斑轴是如何调节的,它如何参与从非粘着斑到粘着斑的进展,
在体内的侵袭性到侵袭性癌症或它如何与先前确定的机制协调,以促进
侵袭性进展。这是一个关键的知识差距,因为没有对这些问题的清晰理解,
然而,我们无法开发治疗策略来靶向这一途径并防止进展到
致命的侵袭性膀胱癌这一建议的具体目标是确定这部小说的作用
TRIM 29-侵袭性进展中的粘着斑轴,并利用这一知识开发治疗
阻断高风险TRIM 29+肿瘤侵袭性进展的策略。核心假设是TRIM 29
通过驱动中间丝,推动非侵入性膀胱癌发展为致命的侵入性膀胱癌
和粘着斑形成,以及在侵袭性细胞中FAK/Src信号传导的激活。这一假设将
具体测试目标如下:1)对TRIM 29进行详细的结构-功能分析
与中间丝的相互作用,粘着斑复合物,和FAK/Src信号在入侵。(二)
确定膀胱癌发生过程中对TRIM 29、KRT 14和黏着斑蛋白的需求
和侵入性进展。3)评估阻断TRIM 29介导的侵袭的新的治疗策略,
膀胱癌目标1将利用活细胞成像,3D和动物模型的入侵。Aim 2将利用
膀胱癌的独特GEMM来剖析TRIM 29在体内的基本功能。Aim 3将使用我们的
多个模型来鉴定靶向TRIM 29介导的侵袭的治疗策略。本研究是
在概念上创新的一种新的TRIM 29-局灶性粘附途径的表征侵袭性
在开发新型膀胱癌小鼠模型方面取得了进展和技术创新,
3D肿瘤侵袭测定和新的治疗靶向策略。所提出的研究是有意义的
因为TRIM 29介导的侵袭性进展机制的描述将允许鉴定
新的治疗策略,以阻止膀胱癌中致命的侵袭性进展的发展。
项目成果
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PHILLIP L PALMBOS的其他文献
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{{ truncateString('PHILLIP L PALMBOS', 18)}}的其他基金
Mechanism and Therapeutic Targeting of TRIM29-mediated Invasion in Bladder Cancer
TRIM29介导的膀胱癌侵袭的机制和治疗靶向
- 批准号:
10667609 - 财政年份:2022
- 资助金额:
$ 43.99万 - 项目类别:
Regulation of ATDC by TP63 and its role in bladder cancer
TP63对ATDC的调控及其在膀胱癌中的作用
- 批准号:
9979790 - 财政年份:2016
- 资助金额:
$ 43.99万 - 项目类别:
Regulation of ATDC by TP63 and its role in bladder cancer
TP63对ATDC的调控及其在膀胱癌中的作用
- 批准号:
9763474 - 财政年份:2016
- 资助金额:
$ 43.99万 - 项目类别:
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