Ovarian cancer is the most lethal gynecological malignancy and is the 5th most frequent cause of cancer-related deaths among women in the US. Nearly 70% of women are diagnosed with advanced, incurable stages of the disease. Efforts to better treat ovarian cancer hinge upon having an accurate understanding of the cellular, molecular and genetic events leading to the disease. Recent extensive studies of a large number of the most common and aggressive type of ovarian cancer, high-grade serous carcinoma (HGSOC), have described a broad repertoire of genomic alterations common for this disease. Unfortunately, practical utilization of this information is hindered because the originating cells are not established. While some investigators contend that malignancies originate from the ovarian surface epithelium (OSE), others believe that they originate from the tubal (Fallopian) epithelium (TE). Recently we have discovered stem cell niches located at the junctions between OSE, mesothelium and TE. We have also shown that HGSOC may preferentially originate from these stem cell niches. However, some cancers may also arise from more differentiated cells. It is unknown if the cell of origin may pre-program biological behavior of ovarian cancer. Furthermore, it is also unclear if the development of different types of ovarian carcinomas, such as high and low grade serous and endometrioid carcinomas, depends on the transformation of cells at a particular stage of their differentiation.
We plan to address these questions by joint efforts of laboratories at Cornell University and Weill Cornell Medical College. The PIs of these laboratories have long-standing interest in cancer research and reproductive biology. The combination of their unique expertise in ovarian cancer research (Drs. Nikitin and Ellenson), stem cell biology (Dr. Nikitin), genomics (Dr. Schimenti) and surgical and comparative pathology (Drs. Nikitin and Ellenson) enables a synergistic interaction and multidisciplinary approach to the problem. The research team has a track record of previous successful collaborations and operates in a highly supportive institutional environment. We expect that our research will significantly improve our understanding of ovarian carcinoma pathogenesis and lead to identification of early critical drivers of this malignancy. Our findings also will stimulate targeted searches for preneoplastic/early neoplastic lesions in the areas of transition between OSE, mesothelium and TE in humans. Successful development of this project is expected to lay the basis for translational studies, such as identification of unique biomarkers and therapeutic targets based on stratification of ovarian carcinoma according to their cell of origin and causative genetic alterations. The funding of the current proposal will provide us with the necessary leverage to compete successfully for an NCI or DOD funded program project grant.
This grant was made possible in part by a generous donation from the Randall and Barbara Smith Foundation.
- Lora Hedrick Ellenson, MD, Cornell University
- John Schimenti, PhD, Cornell University