The role and therapeutic potential of ZNF304 in Ovarian Cancer Through siRNA lethality screening, we recently discovered that ZNF304 gene, a novel transcription factor, is required for ovarian cancer survival. More importantly, we found that expression of ZNF304 gene is significantly associated with poor prognosis and markedly shorter overall survival (OS) of ovarian cancer patients when we analyzed The Cancer Genome Atlas (TCGA) ovarian cancer patient database (n=500). We also found that ZNF304 protein is highly overexpressed in all 5 different ovarian cancer cells including paclitaxel and cisplatin resistant clones and its expression was not detectable normal ovarian epithelium. In vitro silencing of ZNF304 by siRNA significantly inhibited cell proliferation and invasion of ovarian cancer cells, suggesting that ZNF304 may be an important gene driving ovarian cancer progression and transformation thus may be an potential therapeutic target in ovarian cancer. We hypothesize that ZNF304 expression is involved in disease progression by driving expression of critical cellular proteins that promote cell proliferation, survival and invasion/ metastasis in ovarian cancer cells. We also hypothesize that that ZNF304 is potential novel molecular target in ovarian cancer due to its clinical significance and multiple effects in regulation of critical cellular proteins and signaling pathways. Thus therapeutic silencing of this gene by systemically administered siRNA nanotherapeutics will effectively inhibit tumor growth and enhance efficacy of standard chemo therapies in human metastatic ovarian cancers orthotopic models.
In specific aim 1, we will determine the role and molecular mechanism of ZNF304-induced proliferation, invasion and ovarian cancer cells.
In aim 2, we will determine therapeutic potential of ZNF304 and validate it as a molecular target in ovarian cancer models by therapeutically targeting it systemically administered tumor-targeting siRNA nanotherapeutics in ovarian cancer models. For this purpose we will generate regular and AXL-specific thioaptamer-conjugated nanoliposomal vectors incorporating ZNF304 siRNA to target siRNA vectors to ovarian tumors and also provide dual anti-tumor effect strategy as AXL kinase, which is a molecular target associated with shorter patient survival based on our preliminary data. Understanding the role of ZNF304 in ovarian cancer biology, poor prognosis and therapeutic potential would provide foundation for focusing further on this gene and developing clinically applicable therapeutic approaches.
We discovered that ZNF304 is a highly overexpressed gene in patients with ovarian cancer and associated with poor prognosis and shorter survival. ZNF304 gene codes a novel transcription factor, which is one of the zinc finger proteins constituting the largest class of transcription factors encoded by human genome and its role in initiating or promoting ovarian and cancers is largely unknown. The goal of this project is to determine the role of ZNF304 in ovarian cancer tumor growth and metastasis as well as its value as a novel therapeutic target using new class of drugs called siRNA-therapeutics in ovarian cancer models.
|Rodriguez-Aguayo, Cristian; Monroig, Paloma Del C; Redis, Roxana S et al. (2017) Regulation of hnRNPA1 by microRNAs controls the miR-18a-K-RAS axis in chemotherapy-resistant ovarian cancer. Cell Discov 3:17029|
|Shahbazi, Reza; Ozpolat, Bulent; Ulubayram, Kezban (2016) Oligonucleotide-based theranostic nanoparticles in cancer therapy. Nanomedicine (Lond) 11:1287-308|
|Gonzalez-Villasana, Vianey; Fuentes-Mattei, Enrique; Ivan, Cristina et al. (2015) Rac1/Pak1/p38/MMP-2 Axis Regulates Angiogenesis in Ovarian Cancer. Clin Cancer Res 21:2127-37|
|Aslan, Burcu; Monroig, Paloma; Hsu, Ming-Chuan et al. (2015) The ZNF304-integrin axis protects against anoikis in cancer. Nat Commun 6:7351|
|Ozcan, Gulnihal; Ozpolat, Bulent; Coleman, Robert L et al. (2015) Preclinical and clinical development of siRNA-based therapeutics. Adv Drug Deliv Rev 87:108-19|
|Gonzalez-Villasana, Vianey; Rodriguez-Aguayo, Cristian; Arumugam, Thiruvengadam et al. (2014) Bisphosphonates inhibit stellate cell activity and enhance antitumor effects of nanoparticle albumin-bound paclitaxel in pancreatic ductal adenocarcinoma. Mol Cancer Ther 13:2583-94|
|Zhaorigetu, Siqin; Rodriguez-Aguayo, Cristian; Sood, Anil K et al. (2014) Delivery of negatively charged liposomes into the atherosclerotic plaque of apolipoprotein E-deficient mouse aortic tissue. J Liposome Res 24:182-90|
|Ozpolat, Bulent; Sood, Anil K; Lopez-Berestein, Gabriel (2014) Liposomal siRNA nanocarriers for cancer therapy. Adv Drug Deliv Rev 66:110-6|
|Aslan, Burcu; Ozpolat, Bulent; Sood, Anil K et al. (2013) Nanotechnology in cancer therapy. J Drug Target 21:904-13|