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Role of MTF1 in ovarian cancer

MTF1 在卵巢癌中的作用

基本信息

批准号：
9750254
负责人：
Junming Yue
金额：
$ 17.23万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-24 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9750254
关键词：
Binding Proteins Biological Assay Biological Markers CA-125 Antigen CRISPR/Cas technology Cancer Model Cancer Patient Cell Cycle Cell Cycle Proteins Cell Proliferation Cell Survival Cells Cessation of life Clinical Clinical Trials Colon Carcinoma Copper Diagnosis Disease-Free Survival Drug Targeting Endonuclease I Epithelium FDA approved Female Genes Genetic Transcription Goals Heavy Metals Homeostasis Hypoxia Invaded Knock-out Luciferases Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Malignant neoplasm of ovary Matrix Metalloproteinases Mesenchymal Metallothionein Metals Modeling Molecular Mus Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Oncogenes Organ Ovarian Oxidative Stress Pathway interactions Peritoneal Fluid Pharmaceutical Preparations Phase Physiological Proteins Recurrence Regulator Genes Reporter Genes Reporting Research Project Grants Resistance Role TP53 gene Testing Therapeutic Time Translational Research Woman Zinc Zinc Fingers base c-myc Genes cancer cell cancer diagnosis cancer therapy cell growth chromatin immunoprecipitation epithelial to mesenchymal transition functional loss in vivo Model inhibitor/antagonist innovation leukemia loss of function migration mouse model neoplastic cell novel novel strategies ovarian neoplasm overexpression pre-clinical small molecular inhibitor small molecule inhibitor therapeutic evaluation therapeutic target transcription factor transcription factor MTF-1 tumor tumor growth tumor xenograft

项目摘要

Ovarian cancer is the deadliest gynecological malignancy in women. However, therapeutic options for ovarian cancer are limited due to chemotherapeutic resistance, frequent recurrence, and metastasis. However, the underlying molecular mechanisms involving in ovarian cancer metastasis and chemoresistance is largely elusive. Metal responsive transcriptional factor 1 (MTF1) is a zinc finger transcriptional regulator and is significantly amplified or upregulated in ovarian cancer, which is associated with diminished disease-free survival. However, the role of MTF1 in ovarian cancer is completely unknown. This proposal is to test how MTF1 contributes to ovarian cancer metastasis and chemoresistance and test an FDA approved phase I drug APTO-253 for leukemia as a MTF1 small inhibitor in ovarian cancer treatment. We have found that MTF1 is a key regulator of the cell cycle in ovarian cancer cells and that inhibition of MTF1 using its small molecular inhibitor APTO-253 leads to reduced ovarian cancer cell proliferation, migration, and invasion. The expression of the CDK6 cell cycle protein was inhibited while p21 upregulated. In particular, APTO-253 inhibits cMyc expression and induces p53 expression. Moreover, we found that APTO-253 inhibits epithelia to mesenchymal transition (EMT) in ovarian cancer. Our preliminary studies implicated that MTF1 is a potential drug target in treating ovarian cancer. To define the role of MTF1 and its potential in treating ovarian cancer we propose two specific aims: 1) Test the hypothesis that MTF1 expression is transcriptionally activated by transcriptional factors and determine the regulatory network of MTF1 in ovarian cancer. 2) Test the hypothesis that inhibition of MTF1 suppresses tumor cell growth and tumor metastasis and also overcomes chemoresistance. This is an innovative and significant translational research project to investigate the MTF1 regulatory network using gain and loss of function approaches. In particular, testing a MTF1 small molecular inhibitor APTO-253, an FDA approved phase 1 drug in ovarian mouse model cancer will provide the experimental evidence for ovarian cancer treatment.

卵巢癌是女性最致命的妇科恶性肿瘤。然而，卵巢癌的治疗选择癌症由于化疗抗性、频繁复发和转移而受到限制。但涉及卵巢癌转移和化疗耐药的潜在分子机制在很大程度上是难以捉摸的。金属应答转录因子1（MTF 1）是一种锌指转录调控因子，在转录水平上与转录因子的表达有显著的相关性。在卵巢癌中扩增或上调，这与无病生存率降低有关。然而，在这方面， MTF 1在卵巢癌中的作用完全未知。本提案旨在测试MTF 1如何有助于卵巢癌转移和化疗耐药性，并测试FDA批准的用于白血病的I期药物APTO-253 在卵巢癌治疗中作为MTF 1小抑制剂。我们发现MTF 1是细胞的关键调节因子，在卵巢癌细胞中的细胞周期和使用其小分子抑制剂APTO-253抑制MTF 1导致降低卵巢癌细胞增殖、迁移和侵袭。CDK 6细胞周期蛋白的表达 p21表达上调。特别地，APTO-253抑制cMyc表达并诱导p53 表情此外，我们发现APTO-253抑制卵巢上皮细胞向间质转化（EMT），癌我们的初步研究表明，MTF 1是一个潜在的药物靶点，在治疗卵巢癌。到为了明确MTF 1的作用及其在治疗卵巢癌中的潜力，我们提出了两个具体目标：1）检测假设MTF 1表达是由转录因子转录激活的，并决定了 MTF 1在卵巢癌中的调控网络。2)测试抑制MTF 1抑制肿瘤的假设细胞生长和肿瘤转移，并且还克服化学抗性。这是一个具有创新意义的一个转化研究项目，利用功能的获得和丧失来研究MTF 1调控网络接近。特别是，测试MTF 1小分子抑制剂APTO-253，一种FDA批准的1期药物，卵巢癌小鼠模型的建立将为卵巢癌的治疗提供实验依据。