Developing a targeted chemoprevention strategy for Non-Small Cell Lung Cancer
Developing a targeted chemoprevention strategy for Non-Small Cell Lung Cancer
批准号:
9170948
负责人:
BRIGITTE N GOMPERTS
金额:
$35.23万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-08-15 至 2021-07-31
关键词:
ABL1 geneABL2 geneAddressBindingBiologyCarcinomaCell ProliferationCell SurvivalCellsChemopreventionComplexDevelopmentE-CadherinEnvironmentEpithelialGoalsHistologicImmunofluorescence ImmunologicInjuryLeadLesionLibrariesLungMalignant neoplasm of lungMass Spectrum AnalysisMutateMutationNatural regenerationNon-Small-Cell Lung CarcinomaNuclearPathway interactionsPatientsPharmaceutical PreparationsPhosphorylationPhosphorylation SitePhosphotransferasesPreclinical Drug EvaluationPremalignantProcessProteinsResearchResolutionRoleSignal PathwaySignal TransductionSiteSite-Directed MutagenesisSmall Interfering RNASmokingStaining methodStainsStem cellsTissue MicroarrayTissuesToxic effectTyrosineTyrosine Phosphorylation Siteabstractingairway epitheliumbeta catenincancer subtypesinjury and repairnovel chemopreventionnovel strategiespreventrepairedself-renewalsmall molecule
中文摘要
项目摘要/摘要:
--
肺癌被认为是以一种循序渐进的方式发展起来的,这给了我们在它变得更好之前进行干预的机会。
侵入性。因此,需要一种新的方法来治疗肺癌患者,因此需要开发一种有针对性的化学预防方法。
预防肺癌和癌前病变形成的策略是当务之急。我的实验室正在研究呼吸道和基底动脉干。
细胞修复(ABSCs)和其他信号通路参与了损伤后细胞修复和再生过程。我们的研究表明。
美国同意这一结论,即癌前病变代表着ABSCs过度自我更新的状态,并导致ABA的严重障碍。
我们已经确定了几种分化机制,它们参与了从鳞状细胞到肺鳞状细胞的逐步进展。
癌症。一种这样的机制涉及到ABSCs通过Wnt-β-catenin途径的增殖抑制,特别是通过这种途径。
我们还发现,只有三分之一的差异酪氨酸和磷酸化位点是由β-连环蛋白的Y489和残基组成。
允许对β进行核本地化处理,同时允许Tcf/LEF进行核扩散激活处理。我们已经发现了这一点。
经典地描述为β的其他蛋白质的磷酸化过程--连环蛋白的磷酸化位点只会导致膜性改变。
β-连环蛋白的本地化研究。在正常情况下,β-连环蛋白489位(p-β-连环蛋白Y489)的主要磷酸化产物不存在。
呼吸道ABSCs的功能和功能仅在损伤后的正常修复过程中短暂开启,但在癌前病变中仍持续存在。
ABSCs在肺鳞癌和肺癌(SLC)中发现了一组细胞亚群。
我们的下一个目标是进一步了解推动β--连环蛋白在489日元的磷酸化水平的主要机制,并发现。
化合物需要防止这一过程。这项研究将使我们能够更好地防止癌前疾病的过度扩散。
并为SLC开发一种全新的化学预防和战略规划。我们将继续实现这一目标,实现以下目标:*
具体目标1:进一步了解p-β-cateninY489基因在ABSC、癌前病变和癌前病变的增殖过程中的重要作用。
肺癌和癌症。我们假设,在所有的组织学中,p-β-y489是一种常见的细胞增殖机制。
肺癌和癌症的不同亚型。
具体目标2:进一步确定ABSCs中负责β--连环蛋白Y489位点磷酸化的蛋白激酶/S。
假设有一种特定的蛋白激酶/S说,在他驱动的第二个Y489位点上,可能会磷酸化β-连环蛋白。
ABSCs的增殖有助于形成癌前病变。
具体目标3:进一步确定可预防β-cateninY489的化合物。我们将进行一次有针对性的筛查。
可以防止ABSCs中TCF/LEF激活的化合物以及新的毒性筛查。这一技术将使我们能够更好地识别。
可以抑制细胞增殖的化合物,但不会对ABSC产生毒性。我们将从这一初级筛查中发现一些化合物。
将被带到一个新的二级筛查系统上,该筛查系统具有免疫荧光法,用于检测p-β-连环蛋白Y489。
我们的团队成就卓著,是加州大学洛杉矶分校最杰出的生物环境专家,也是最重要的生物生物学专家。
在这项新提案中得到解决后,所有这些都将提供极高的可能性,即这一NCI的挑衅性问题将不会被解决。
回答了在非小细胞肺癌和癌症治疗中针对癌前疾病的研究,并领导了一项有针对性的研究的未来发展计划。
肺癌的化学预防和战略研究表明,这将挽救数百万人的生命。
英文摘要
Project Summary/Abstract
Lung cancer is thought to develop in a stepwise fashion giving us the opportunity to intervene before it becomes
invasive. A novel approach to cure patients of lung cancer is therefore to develop a targeted chemoprevention
strategy to prevent the formation of lung premalignant lesions in the first place. My lab studies airway basal stem
cells (ABSCs) and the signaling pathways involved in their repair and regeneration after injury. Our studies led
us to the conclusion that premalignancy represents a state of excessive self-renewal of ABSCs with a block in
differentiation and we identified several mechanisms involved in stepwise progression to Squamous Lung
Cancer. One such mechanism involves proliferation of ABSCs via the Wnt-β-catenin pathway and in particular
we found that only one of the differential phosphorylation sites, the tyrosine Y489 residue of the β-catenin protein,
allowed nuclear localization of β-catenin with concomitant TCF/LEF activation for proliferation. We found that
phosphorylation of other classically described β-catenin phosphorylation sites only resulted in membranous
localization of β-catenin. The phosphorylation of β-catenin at Y489 (p-β-cateninY489) is not present in normal
airway ABSCs and is turned on only briefly during normal repair after injury, but it persists in premalignant lesion
ABSCs and in a subset of cells in Squamous Lung Cancer (SLC).
Our goal is to understand the mechanisms that drive phosphorylation of β-catenin at Y489 and discover
compounds to prevent this process. This will allow us to prevent the excessive proliferation of premalignancy
and develop a novel chemoprevention strategy for SLC. We will achieve this goal with the following aims:
Specific Aim 1: To understand the role of p-β-cateninY489 in proliferation of ABSCs, premalignant lesions and
lung cancers. We hypothesize that p-β-cateninY489 is a common mechanism for proliferation in all histologic
subtypes of lung cancer.
Specific Aim 2: To identify the kinase/s responsible for phosphorylation of β-cateninY489 site in ABSCs. We
hypothesize that there are specific kinase/s that phosphorylate β-catenin at the Y489 site which drives
proliferation of ABSCs to form premalignant lesions.
Specific Aim 3: To identify compounds that prevent p-β-cateninY489. We will perform a targeted screen of
compounds that prevent TCF/LEF activation in ABSCs along with a toxicity screen. This will allow us to identify
compounds that inhibit proliferation but are not toxic to ABSCs. Lead compounds from this primary screen will
be taken to a secondary screen with immunofluorescence for p-β-cateninY489.
Our highly accomplished research team, the outstanding environment at UCLA and the important biology that is
being addressed in this proposal all provide a high likelihood that this NCI Provocative Question 1 will be
answered for targeting premalignancy in Non-Small Cell Lung Cancer and lead to the development of a targeted
chemoprevention strategy for Lung Cancer that will save millions of lives.
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