FHIT Gene Therapy in Cancer Prevention and Treatment
FHIT 基因疗法在癌症预防和治疗中的应用
基本信息
- 批准号:7211572
- 负责人:
- 金额:$ 22.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-12-01 至 2011-11-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAllelic ImbalanceAnimalsApoptosisBirthCancer ModelCarcinogen exposureCarcinogensCarcinomaCell CycleCellsChromosomal InstabilityChromosome Fragile SitesComplexDNA DamageDNA Double Strand BreakDNA biosynthesisDevelopmentDiagnostic Neoplasm StagingDisease regressionDisease remissionDoseDrug Delivery SystemsEffectivenessEsophagealEtiologyEventExhibitsExposure toFHIT geneFutureGastrointestinal tract structureGatekeepingGene MutationGenesGeneticGenomic InstabilityGenotypeGoalsHeterogeneityHumanHyperplasiaImmunohistochemistryInduction of ApoptosisLeadLesionLungMalignant NeoplasmsMalignant neoplasm of cervix uteriMalignant neoplasm of esophagusMouse StrainsMouth NeoplasmsMusMutagensMutationNatureNeoplasmsNeoplastic ProcessesNitroquinolinesOralOral cavityOrganOxidesPapillomavirusPathway interactionsPhosphorylationPre-Clinical ModelPredispositionPremalignantPreventionProteinsProtocols documentationRecombinantsRecurrenceReportingResearchResearch PersonnelResearch Project GrantsScheduleSignal PathwaySignal TransductionSkinStomach NeoplasmsStressSuppressor MutationsTP53 geneTestingTimeTissuesTobacco-Associated CarcinogenTreatment ProtocolsTumor BurdenTumor Suppressor ProteinsUpper aerodigestive tract cancerWild Type Mousebasecancer cellcancer preventioncancer therapygene therapyhuman 53BP1 proteinmalignant mouth neoplasmmouse modelneoplasticneoplastic celloral lesionpre-clinicalpressurepreventprogramsprotein expressionresearch studyresponsetherapeutic targettumor
项目摘要
DESCRIPTION (provided by applicant): FHIT Gene Therapy in Cancer Prevention and Treatment. We have developed murine upper digestive tract cancer models induced by oral /V-nitrosomethylbenzylamine (NMBA) or 4-nitroquinoline 1-oxide (NQO) treatment. Wild type (WT) mice are not very susceptible to these carcinogens but mice deficient for either Fhit or p53 develop a tumor burden up to 10 times greater than WT mice on exposure to NMBA or NQO, on predictable schedules. Mouse forestomach tumor burden is dramatically reduced by FHIT therapy early (tumor prevention) or late (tumor regression) after carcinogen exposure, and lung and cervical cancer studies are in progress. A caveat to mouse preclinical models is the prevailing notion that mouse tumors exhibit less genetic complexity and heterogeneity than human counterparts, so that human cancers may be less responsive to FHIT gene therapy. The proposed study aims to address this concern by testing FHIT gene therapy in genetically complex mouse tumors in the recombinant mouse cross, FhitxTrp53, with induced forestomach and oral cancers, to show that Fhit, as a gatekeeper gene product whose loss initiates the neoplastic process, can prevent or reverse tumors after AAVFHIT delivery. The FHIT locus is exquisitely susceptible to replication damage on exposure to genotoxic agents and Fhit protein is lost or reduced early in development of precancerous lesions of upper aerodigestive tract tumors. Research in this Project is based on the hypotheses that replacement of FHIT in these lesions could: a) eradicate the altered cells in the "cancer field" of these organs, thus preventing recurrences; b) reverse progression of established cancers; c) allow identification of pathways altered by Fhit loss during development of preneoplasia in Fhit deficient animals, before and after FHIT gene therapy, and of protein targets for pharmacological reactivation of Fhit signal pathways. Thus, the aims of this research project are to: 1) prevent and reverse preneoplastic and neoplastic lesions, respectively, in forestomachs of Fhit and Fhitp53 mice by FHIT gene therapy; 2) optimize the protocol for NQO induction of oral cancers in the tumor suppressor deficient mice and prevent and reverse preneoplasias and neoplasias of the oral cavity in Fhit and Fhitp53 mice by FHIT gene therapy; 3) "cure" the Fhit and Fhit/p53 deficient mice of NMBA and NQO-induced lesions by multiple FHIT gene therapy doses or FHIT gene therapy plus Fhit pathway targeted drug treatment. In each specific aim Fhit-/- mice will be included and tissues from mice with and without FHIT gene therapy will be assessed for expression of cell cycle, DNA damage response and apoptosis-associated proteins, as well as Fhit- interacting proteins to identify the signal pathways altered by Fhit absence, restored by Fhit replacement, and likely to serve as drug targets for treatment of upper digestive tract and other cancers.
描述(由申请人提供):FHIT基因治疗在癌症预防和治疗中的应用。我们已经建立了口服N-亚硝基甲基苄胺(NMBA)或4-硝基喹啉1-氧化物(NQO)治疗诱导的小鼠上消化道癌模型。野生型(WT)小鼠对这些致癌物不是很敏感,但Fhit或p53缺陷的小鼠在可预测的时间表上暴露于NMBA或NQO时产生的肿瘤负荷比WT小鼠高10倍。小鼠前胃肿瘤负荷显着降低FHIT治疗早期(肿瘤预防)或晚期(肿瘤消退)后,致癌物暴露,肺癌和宫颈癌的研究正在进行中。对小鼠临床前模型的一个警告是流行的观点,即小鼠肿瘤表现出比人类肿瘤更少的遗传复杂性和异质性,因此人类癌症可能对FHIT基因治疗的反应较低。拟议的研究旨在解决这一问题,通过测试FHIT基因治疗在遗传复杂的小鼠肿瘤中的重组小鼠杂交,FhitxTrp 53,诱导前胃癌和口腔癌,以显示Fhit,作为一个看门人基因产物,其损失启动肿瘤过程,可以预防或逆转肿瘤后AAVFHIT交付。FHIT基因座在暴露于遗传毒性剂时对复制损伤非常敏感,并且Fhit蛋白在上呼吸消化道肿瘤的癌前病变的发展早期丢失或减少。该项目的研究基于以下假设:在这些病变中替换FHIT可以:a)根除这些器官的“癌区”中的改变的细胞,从而防止复发; B)逆转已建立的癌症的进展; c)允许在FHIT基因治疗之前和之后,在Fhit缺陷动物中瘤前形成的发展期间,鉴定由Fhit损失改变的途径,和Fhit信号通路的药理学再活化的蛋白质靶点。因此,本研究项目的目的是:1)通过FHIT基因治疗分别预防和逆转Fhit和Fhitp 53小鼠前胃的癌前病变和肿瘤病变:2)优化NQO诱导肿瘤抑制基因缺陷小鼠口腔癌的方案,并通过FHIT基因治疗预防和逆转Fhit和Fhitp 53小鼠口腔的癌前病变和肿瘤病变; 3)通过多次FHIT基因治疗剂量或FHIT基因治疗加Fhit通路靶向药物治疗“治愈”Fhit和Fhit/p53缺陷小鼠的NMBA和NQO诱导的病变。在每个特定目标中,将包括Fhit-/-小鼠,并且将评估来自具有和不具有FHIT基因疗法的小鼠的组织的细胞周期、DNA损伤应答和凋亡相关蛋白以及Fhit相互作用蛋白的表达,以鉴定由Fhit缺失改变、由Fhit替代恢复并且可能用作治疗上消化道和其他癌症的药物靶标的信号途径。
项目成果
期刊论文数量(0)
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