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.
The proposed project aims to define the role of transcriptional factor MTF1 in ovarian cancer by using gain and loss of functional approaches and test the therapeutic potential of MTF1 small molecule inhibitor in orthotopic ovarian cancer mouse model.
|Dong, Peixin; Xiong, Ying; Yue, Junming et al. (2018) Long Non-coding RNA NEAT1: A Novel Target for Diagnosis and Therapy in Human Tumors. Front Genet 9:471|
|Wang, Baojin; Li, Xia; Zhao, Guannan et al. (2018) miR-203 inhibits ovarian tumor metastasis by targeting BIRC5 and attenuating the TGF? pathway. J Exp Clin Cancer Res 37:235|