Abstract
High grade serous ovarian cancer remains the deadliest of gynecological cancers. Therefore, a better understanding of the molecular events that promote and maintain high grade serous ovarian cancer is necessary to develop new targeted therapy. It is becoming increasingly clear that aberrantly activated or expressed transcription factors play key roles in tumorigenesis by driving tumorigenic phenotypes through modulation of downstream target genes, some of which are transcription factors themselves developing large transcription factor networks. Thus, we hypothesized that targeting one or more aberrantly expressed transcription factor which represent key nodes in transcription factor networks may provide a new avenue for targeted ovarian cancer therapy. To identify such factors, we analyzed genetic abnormalities in transcription factors in ovarian tumors from The Cancer Genome Atlas (TCGA) and ovarian cancer cell lines from the Cancer Cell Line Encyclopedia, and identified the oncogenic transcriptional modulator BCL6 as being amplified in approximately 25% of ovarian cancer patients and cell lines. We have found that BCL6 is expressed and activated in the majority of ovarian cancer cell lines tested. In addition, we determined that inhibition of BCL6 via siRNA or pharmacologic inhibition reduced the viability of ovarian cancer cell lines and cells from primary ovarian tumors. Moreover, we have utilized a three dimensional model of ovarian cancer to better recapitulate the clinical characteristics of ovarian tumors in vitro. Utilizing this system, we found that BCL6 expression was necessary for the formation of spheroids, which are similar in appearance to the in vivo growth of ovarian cancer. Given this important role of BCL6 in ovarian cancer, we next wanted to determine if BCL6 amplification was associated with other genetic features of high grade serous ovarian cancer. Analysis of ovarian cancer tumors from TCGA determined that BCL6 amplification was significantly associated with Myc amplification. To determine if BCL6 and Myc were part of the same transcription factor network, we utilized available ChIP-seq data to determine if there were overlapping binding regions between these factors. We identified over 200 regions within the genome where BCL6 and Myc binding regions overlapped suggesting that they modulate a subset of the same genes. Analysis of both cell lines and primary ovarian cancer by ChIP confirmed that BCL6 and Myc bind to a subset of overlapping regions. Additionally, a number of genes associated with these binding sites were modulated upon BCL6 and Myc inhibition, demonstrating that these factors are part of an overlapping transcription factor network. Importantly, co-treatment of ovarian cancer cell lines with BCL6 and Myc inhibitors resulted in enhanced loss of cell viability suggesting that combination therapy that targets multiple nodes in a network (such as BCL6 and Myc) may be an effective treatment option. Thus, analyzing the interrelationship among oncogenic transcription factors can shed light on ovarian cancer pathogenesis and also aid in the development of novel treatment strategies for ovarian cancer.
Citation Format: Sarah R. Walker, Yixi Zhang, Katarina Bartel, Yasmin Kroll, David A. Frank. Targeting transcriptional networks for ovarian cancer therapy. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A46.
