Ovarian cancer is a devastating disease that afflicts approximately 22000 women and causes approximately 15,000 deaths in the United States each year. Progress has been made over the last three decades with improved 5-year survival due to better surgery and chemotherapy, but the overall cure rate remains an unacceptable 33%. Thus, there are pressing requirement for identification of novel biomarkers for prognosis and new therapeutic targets that can be used to improve outcome for ovarian cancer patients. ceRNA is a type of RNA that binds and inactivates microRNA (miR). Since miR have important roles in the initiation and progression of ovarian cancer, ceRNA could be an important regulator in ovarian cancer. The role of ceRNA in the regulation of miR in ovarian cancer represents an understudied opportunity to generate new biomarkers and new therapeutic opportunities.
Locus 3q26.2 of Chromosome 3, is highly amplified in a subset of high-grade serous epithelial ovarian cancer (HGSEOC), making it the most common copy number abnormality in the most aggressive and lethal form of ovarian cancer. Copy number variations (CNVs), a form of structural variation of the DNA in the cell, are frequent events in ovarian cancer. CNVs alter the amount of DNA for genes leading to changes in amounts of the proteins that influence the growth and behavior of ovarian cancer cells. Protein coding regions in CNVs have been well studied and characterized by our and other laboratories. Our high-throughput and high-resolution analysis recently showed that non-coding microRNAs named miR569 and miR551b in the 3q26.2 CNV are highly amplified and highly expressed in HGSEOC. Using cellular and molecular approaches we demonstrated the underlying oncogenic mechanism of action both miR569 and miR551b in ovarian cancer.
In the proposed study we will characterize the novel role of the CLDN11 gene, which is located close to miR569 and miR551b in the 3q26.2 locus. Our preliminary data demonstrates a novel action of CLDN11 mRNA on miR dynamics, that we have designated the ‘CLDN11 ceRNA effect’, which provides a growth advantage to ovarian cancer cells. Briefly, CLDN11 ceRNA acts as a sponge, which binds and inactivates important tumor suppressor microRNAs. Our studies will characterize the mechanism how CLDN11 ceRNA hijacks several tumor suppressor miR, and in turn increases the expression of important oncogenes resulting in activation of key tumorigenic pathways. Thus targeting CLDN11 ceRNA effect has the potential to inhibit the growth and metastasis of ovarian cancer cells. The role of ceRNA in human cancer is only beginning to emerge, thus our studies will provide novel therapeutic opportunities and biomarkers in ovarian cancer.
Dr. Pradeep Chaluvally-Raghavan is an Associate Professor and the Linda and Herbert Buchsbaum, MD, Chair in Gynecologic Oncology in the Department of Obstetrics and Gynecology at the Medical College of Wisconsin. Dr. Chaluvally-Raghavan received his Liz-Tilberis Career Development award in 2016 while working as an Instructor at the MD Anderson Cancer Center. Liz-Tilberis grant facilitated his transition from Instructor to Assistant Professor in the Department of Obstetrics and Gynecology at the Medical College of Wisconsin in 2016 and subsequently to the rank of Associate Professor in 2020.
Dr. Chaluvally-Raghavan’s research focuses on mechanistic studies determining the role of protein-coding and non-coding genomic aberrations in patient tumors with a focus on RNA Binding Proteins (RBPs) and oncostatin family proteins to develop as therapeutic targets and biomarkers. His research is currently supported by the National Cancer Institute and the Department of Defense’s ovarian cancer program to continue his important work focuses on improving the quality of life of those who afflicted with ovarian cancer.
His research reported the role of dysregulation of FOXM1 and EGFR/ERBB2 signaling on the transition of the adherent form of ovarian tumor cells to become highly metastatic non-adherent cancer cells. They have also reported the mechanism that FXR1, an RNA Binding Protein promotes MYC translation by binding on its 3'UTR, promoting mRNA circularization by enforcing a circular loop between 3' and 5'UTR and also by recruiting eIF4F complex to the translation start site.
In addition to the mechanistic research, his team is developing therapeutic approaches to treat ovarian cancer. Using single-cell RNA sequencing, Dr. Chaluvally-Raghavan’s team identified that OSMR is distinctly expressed in ovarian cancer cells, thus could be targeted to treat ovarian cancer. Because no agents are currently available in the clinic to target OSMR for cancer therapy, his team has developed a monoclonal antibody that can block OSMR-signaling and patented. Dr. Chaluvally-Raghavan is now partnering with industries for future development of their antibody as an investigational drug for clinical trials.