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：
7995225
负责人：
CARLO M CROCE
金额：
$ 22.12万
依托单位：
OHIO STATE UNIVERSITY
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 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7995225
关键词：
Address Allelic Imbalance Animals Apoptosis Birth Cancer Model Carcinogen exposure Carcinogens Carcinoma Cell Cycle Cells Chromosomal Instability Chromosome Fragile Sites Complex DNA Damage DNA Double Strand Break DNA biosynthesis Development Diagnostic Neoplasm Staging Disease remission Dose Drug Delivery Systems Early treatment Effectiveness Etiology Event Exhibits Exposure to FHIT gene Future Gastrointestinal tract structure Gatekeeping Gene Mutation Genes Genetic Genomic Instability Genotype Goals Heterogeneity Human Hyperplasia Immunohistochemistry Induction of Apoptosis Lead Lesion Lung Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of esophagus Malignant neoplasm of lung Mouse Strains Mouth Neoplasms Mus Mutagens Mutation Nature Neoplasms Neoplastic Processes Nitroquinolines Oral Oral cavity Organ Oxides Papillomavirus Pathway interactions Phosphorylation Pre-Clinical Model Predisposition Premalignant Prevention Proteins Protocols documentation Recombinants Recurrence Regimen Reporting Research Research Personnel Research Project Grants Schedule Signal Pathway Signal Transduction Skin Stomach Neoplasms Stress Suppressor Mutations Testing Time Tissues Tobacco-Associated Carcinogen Tumor Burden Tumor Suppressor Proteins Upper aerodigestive tract cancer Wild Type Mouse base cancer cell cancer prevention cancer therapy gene therapy human 53BP1 protein malignant mouth neoplasm mouse model neoplastic neoplastic cell oral lesion pre-clinical pressure prevent programs protein expression research study response therapeutic target tumor

项目摘要

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, Fhit+/-xTrp53+/-, 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 Fhit+/-p53+/-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 Fhit+/-p53+/-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.

FHIT基因治疗预防和治疗。我们已经开发了鼠上消化口服 /V-硝基甲基苯胺（NMBA）或4-硝基喹啉1-氧化物（NQO）诱导的道癌模型治疗。野生型（WT）小鼠不太容易受到这些致癌物的影响，而是缺乏的小鼠 FHIT或p53在暴露于NMBA或NQO时，肿瘤负担比WT小鼠高10倍可预测的时间表。小鼠Fortoromath肿瘤负担大大减轻了FHIT治疗（预防肿瘤）或致癌后（肿瘤消退），肺癌和宫颈癌研究正在进行中。小鼠临床前模型的警告是盛行的观念与人类的遗传复杂性和异质性相比，遗传复杂性和异质性较少，因此人类癌症可能是对FHIT基因疗法的反应较少。拟议的研究旨在通过测试FHIT来解决这一问题重组小鼠交叉中遗传复杂的小鼠肿瘤中的基因治疗，fhit +/- xtrp53 +/-，与诱导的Forestomach和口服癌症，以表明该fhit作为看门人基因产物的损失启动肿瘤过程，可以在Aavfhit递送后预防或反向肿瘤 FHIT基因座非常容易受到暴露于遗传毒性和FHIT的复制损害蛋白质在癌前气管肿瘤的癌前病变的早期丧失或减少。该项目的研究基于以下假设：在这些病变中取代FHIT可以：a）消除这些器官“癌症”中的细胞改变的细胞，从而防止复发； b）反向成熟癌症的进展； c）允许识别在FHIT损失过程中改变的途径 FHIT缺乏动物，FHIT基因治疗和蛋白质的肿瘤发展的发展 FHIT信号途径的药理重新激活的靶标。因此，该研究项目的目的是：1）预防和反向肿瘤和肿瘤通过FHIT基因疗法，分别在Fhit +/-和Fhit +/- p53 +/-小鼠的Forestomachs中的病变； 2）优化 NQO诱导肿瘤抑制器中口服癌症的方案，并预防和反向 FHIT基因治疗中的+/-和FHIT +/-和FHIT +/- p53 +/-小鼠口腔的肿瘤和肿瘤。 3）“治愈” NMBA的FHIT和FHIT/p53小鼠和NQO诱导的病变通过多个FHIT基因治疗剂量或FHIT基因疗法加上靶向药物治疗的FHIT途径。在每个特定目标中 - / - 将包括小鼠，并评估有和没有FHIT基因治疗的小鼠的组织细胞周期，DNA损伤反应和凋亡相关蛋白的表达以及FHIT- 相互作用的蛋白质以识别因缺席而改变的信号途径，并通过更换恢复，并且可能是治疗上消化道和其他癌症的药物靶标。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Replicative Stress and the FHIT Gene: Roles in Tumor Suppression, Genome Stability and Prevention of Carcinogenesis.

DOI：
10.3390/cancers6021208
发表时间：
2014-06-04
期刊：
Cancers
影响因子：
5.2
作者：
Karras JR;Paisie CA;Huebner K
通讯作者：
Huebner K

Effect of zinc supplementation on N-nitrosomethylbenzylamine-induced forestomach tumor development and progression in tumor suppressor-deficient mouse strains.

DOI：
10.1093/carcin/bgq251
发表时间：
2011-03
期刊：
Carcinogenesis
影响因子：
4.7
作者：
J. Sun;James Liu;X. Pan;Donald Quimby;N. Zanesi;T. Druck;G. Pfeifer;C. Croce;L. Fong;
通讯作者：
J. Sun;James Liu;X. Pan;Donald Quimby;N. Zanesi;T. Druck;G. Pfeifer;C. Croce;L. Fong;

Initiation of genome instability and preneoplastic processes through loss of Fhit expression.

DOI：
10.1371/journal.pgen.1003077
发表时间：
2012
期刊：
PLoS genetics
影响因子：
4.5
作者：
Saldivar JC;Miuma S;Bene J;Hosseini SA;Shibata H;Sun J;Wheeler LJ;Mathews CK;Huebner K
通讯作者：
Huebner K

Zinc deficiency activates S100A8 inflammation in the absence of COX-2 and promotes murine oral-esophageal tumor progression.

DOI：
10.1002/ijc.25688
发表时间：
2011-07-15
期刊：
INTERNATIONAL JOURNAL OF CANCER
影响因子：
6.4
作者：
Wan, Shao-Gui;Taccioli, Cristian;Jiang, Yubao;Chen, Hongping;Smalley, Karl J.;Huang, Kun;Liu, Xiu-Ping;Farber, John L.;Croce, Carlo M.;Fong, Louise Y. Y.
通讯作者：
Fong, Louise Y. Y.

Fhit deficiency-induced global genome instability promotes mutation and clonal expansion.

DOI：
10.1371/journal.pone.0080730
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Miuma S;Saldivar JC;Karras JR;Waters CE;Paisie CA;Wang Y;Jin V;Sun J;Druck T;Zhang J;Huebner K
通讯作者：
Huebner K