High-grade serous ovarian carcinoma (HGSC) presents significant clinical and therapeutic challenges. Emerging data from The Cancer Genome Atlas (TCGA) have identified a number of new genetic aberrations but their functional significance and the role they play in early tumorigenesis remains to be determined. In addition, identifying the key genetic lesions responsible for tumor initiation and the specific cell of origin is a priority for ovarian cancer research. Although the traditional model of carcinogenesis has focused on the ovary as a tumor initiation site, recent preclinical and clinical studies have suggested that there are additional sites of origin outside the ovary, namely fallopian tubal secretory epithelial cells (FTSECs). This new model of tumorigenesis has further identified novel entities in the fallopian tube epithelium that represent precursors to invasive carcinoma – the TP53 signature and serous tubal intraepithelial carcinoma (STIC).

Identifying and characterizing the events leading to the development of TP53 signatures and STICs, the critical steps in their transition to malignancy, and novel methods for detecting this transition prior to cancer development are critical for cancer prevention and development of personalized approaches to therapy. We have successfully developed genetic models of de novo HGSC that originate in FTSECs and mimic the key genetic alterations and precursor lesions characteristic of human invasive ovarian cancer. The murine tumors accurately recapitulate the histologic, immunophenotypic (CK-8, STMN1, PAX2, P53, Ki-67, WT1, and CA-125), and genomic alterations observed in human HGSC, thus providing a compelling argument for serous carcinogenesis originating in the FTSEC. Our models serve as a proof-of-concept that high-grade serous “ovarian” cancer can arise from the FTSEC and progress to metastatic disease via pre-invasive lesions, namely the STICs. We are currently using the Pax8-driven system to interrogate the role of TCGA genes that have been identified as being important for serous tumorigenesis. Successful completion of our studies will demonstrate that the fallopian tubal secretory epithelial cell is indeed a cell-of-origin for ovarian and pelvic serous carcinomas in vivo when using the most common key TCGA-based tumor drivers for BRCA and non-BRCA tumors, respectively.

The first goal of our research is be to produce valid models for HGSC tumors. The second is to identify unique characteristics of early serous carcinogenesis in the tube that can be exploited for early detection. The third is to determine the causes of the earliest events preceding malignancy, which will enable more efficient methods of diagnostic imaging and cancer prevention with a focus on the distal fallopian tube. Furthermore, by using a combination of murine model studies and epidemiological data from patients, it will be important to determine if premenopausal women with BRCA mutations can be offered risk-reduction surgery in a multi-step procedure without undergoing surgical menopause and loss of fertility in their younger years.

Citation Format: Ruth Perets, Gregory A Wyant, Anders W Ohman, Sunita R Setlur, Christopher P. Crum, Ronny Drapkin, Daniela M. Dinulescu. Novel strategies for targeting high-grade serous ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-CTRL-1204.