By using genomics approaches and tumor specimens with corresponding clinical data from our ovarian cancer biobank, to investigate for novel mechanisms of ovarian cancer initiation, progression and response to treatment, and to identify markers with early diagnostic and/or prognostic significance for this deadly disease.
Epithelial ovarian cancer (EOC) is a highly metastatic disease that is responsible for more cancer deaths among women in the Western world than all other gynecologic malignancies. EOC lethality primarily stems from the inability to detect the disease at an early stage and the lack of effective therapies for advanced disease. Approximately 70% of patients with advanced-stage EOC have widespread intraperitoneal metastases, including frequent accumulation of ascites within the peritoneal cavity. Thus, management of the metastatic disease becomes a crucial problem for EOC treatment. The research activities in my lab are focused on understanding of the genetic and epigenetic changes associated with EOC dissemination and the identification of novel pro-metastatic target pathways and molecules that could enhance the chances of discovering new and effective therapies.
We have recently identified two members from the RUNX gene family, RUNX1 and RUNX2, as being hypomethylated and overexpressed in pro-metastatic EOC cells. Both these RUNX transcription factors have been found to be involved in diverse developmental processes, ranging from hematopoiesis to neurogenesis, and are increasingly being linked with various human cancers. However, their role in EOC tumorigenesis has been not investigated. It is well known that uncontrolled cell proliferation is a hallmark of cancer cells and that cell migration and invasion represent crucial properties of EOC cells specifically for tumor expansion, progression, and metastasis. Validation of RUNX1 and RUNX2 protein expression by immunohistochemistry was indicative for their strong overexpression in the different serous EOC tumor subtypes (including low- and high-malignant EOC tumors and metastases), when compared to normal ovarian tissue samples. Further, in vitro analyses were indicative for RUNX1 and RUNX2 functional implication in mechanisms of EOC cell proliferation, migration and invasion. We now aim to expand our in vitro observations and using animal models, to investigate in vivo whether RUNX1 and RUNX2 may have any functional significance in serous EOC disease progression.
We have recently identified the GALNT3 gene, a member of the GalNAc-transferases (GalNAc-Ts) gene family, as notably hypomethylated and overexpressed in high-grade serous ovarian tumors, compared to low-malignant potential tumors and normal ovarian tissues, as GALNT3 expression was functionally associated with epithelial ovarian cancer (EOC) cell proliferation, migration and invasion. Moreover, GALNT3 expression significantly correlated with shorter progression-free survival intervals in serous EOC patients with advanced disease. Additionally, shRNA-mediated GALNT3 knockdown was associated with reduced MUC1 protein expression in EOC cells, probably related to destabilization of the MUC1 protein due to lack of GALNT3 glycosylation activity. Taken together, our data were indicative for a strong oncogenic potential of the GALNT3 gene in advanced EOC and suggest that GALNT3 overexpression might contribute to ovarian etiology through aberrant mucin O-glycosylation. We intend to further define the role of GALNT3 in EOC tumor expansion in vivo by performing xenograft experiments in athymic nude mice. By using a glycoproteomics approach, we also aim to analyze the altered O-glycoprotein expression pattern in EOC cells upon GALNT3 knockdown.
Recognition that inherited BRCA1 and BRCA2 mutations are implicated in the cause of disease in a proportion of EOC patients led to the identification of the role of the proteins encoded for by these genes in DNA repair. Cells with defects in DNA repair accumulate genetic abnormalities and may progress to become malignant. However, this DNA repair deficiency makes tumor cells vulnerable to further compromise by therapeutic targeting of other associated pathways, using agents such as poly-ADP ribose polymerase (PARP) inhibitors (PARPIs). PARPIs selectively target homologous recombination (HR)-defective cells and show good clinical activity in hereditary EOC associated with BRCA1 or BRCA2 mutations. Yet, a high proportion (up to 50%) of sporadic EOCs could be deficient in HR due to genetic or epigenetic inactivation of BRCA1/BRCA2 or other HR-related genes; a feature known as "BRCAness". Accumulating evidence suggests that PARPIs may have a wider application in the treatment of sporadic high-grade serous ovarian cancer (HGSOC), which is the most frequent EOC subtype, representing about 70% of all advanced EOCs. Our research is focused in developing predictive tool(s) which may help identify sporadic HGSOC patients, most likely to respond to PARPIs therapy.