Prevention of Ovarian High-Grade Serious Carcinoma by Elucidating its Early Changes (DoD-CDMRP Consortium Grant Award)
The Consortium we have established consists of Johns Hopkins University (JHU), which is the Coordinating Center with 3 cores (Administration [Admin], Pathology [Path] and Biostatistics/Bioinformatics/Epidemiology (BBE]) and 4 Research Sites [JHU, Yale University (YU), Memorial Sloan Kettering Cancer Center (MSKCC) and University of Toronto Health Network (THUN)]. The Consortium is a coordinated, collaborative, interdisciplinary program that brings together a group of highly experienced investigators who have devoted their careers to translational research in ovarian cancer featuring pathology, gynecology, oncology, epidemiology, and molecular genetics. The studies in this Consortium are highly coordinated and interrelated and are centered around one theme, namely the elucidation of the early events of ovarian HGSC. Moreover, various technologies that will be used by different projects will be centralized in the different Research Sites so as to avoid duplication of effort.
Project 1: Morphologic and molecular characterization of precursor lesions
PI: Ie-Ming Shih, MD, PhD (Johns Hopkins University)
Evaluate whether STICs are precursor lesions and not metastases from a primary ovarian HGSC by analyzing STICs from women with concomitant ovarian HGSCs and determining if the ovarian tumors have acquired additional molecular alterations compared to the STICs, which would confirm that STICs are precursor lesions.
Project 2: The relationship between serous tubal intraepithelial carcinoma and invasive pelvic serous carcinoma
PI: Douglas Levine, MD (Memorial Sloan Kettering Cancer Center)
Evaluate all the proposed sites of origin (FTE, OSE, CICs and peritoneum), showing that the morphologic and molecular features of tubal, ovarian and primary peritoneal HGSCs are the same and, in conjunction with Project 1, confirming our hypothesis that many, if not most, HGSCs originate in the fimbria and involve the ovary secondarily.
Project 3: Tumor biology in the initiation of ovarian cancer
PI: Patricia Shaw, MD, FRCP(C) (Princess Margaret Cancer Center, Toronto)
Identify the early molecular changes that precede the development of STICs using gene expression analysis of morphologically normal FTE from high-risk women compared to FTE from normal control specimens and use an in vitro system and mouse model to generate a molecularly defined carcinoma resembling HGSC from FTE and OSE using oncogenes expressed in ovarian carcinoma.
Project 4: Mouse models to investigate the role of ovulation and associated microenvironmental changes in early ovarian carcinogenesis
PI: Tian-Li Wang, PhD (Johns Hopkins University)
Locate and characterize precursor lesions of “ovarian” cancer in a mouse model and explore the role of ovulation and changes in the microenvironment of the ovary and tube in “ovarian” carcinogenesis using human tubal xenografts in nude mice.
Project 5: Comprehensive characterization of precursor lesions in the ovary and fallopian tube in high risk women – identify risk reduction opportunities
PI: Kala Visvanathan, MD (Johns Hopkins University)
Determine the molecular and epidemiologic profile of putative precursor lesions in the fallopian tubes and ovaries from women at high-risk for ovarian cancer. In addition, Project 5 will determine if these biomarkers and associated precursor lesions are modifiable by oral contraceptives (OCPs) or anti-inflammatory agents, as OCPs in particular are known to prevent ovarian cancer and impact survival.