Ovarian cancer is the leading cause of gynecologic cancer death in the United States, responsible for over 22,000 cases per year and over 14,000 deaths. The most common type of ovarian cancer is High Grade Serous Ovarian Cancer (HGSOC). Unfortunately, few therapeutic advances for HGSOC have been forthcoming, and the cornerstone of treatment remains chemotherapy and surgery. Identifying therapeutic targets for this disease represents an urgent medical need.
The genomics revolution has yielded personalized treatments for many cancers which are driven by mutated proteins. But HGSOC seems to lack mutations in DNA regions that code for cancer-promoting genes, and so is not amenable to this scientific or therapeutic approach. Rather, HGSOC seems to be driven by dysfunctional gene expression. In cancer, incorrect gene expression is often mediated by regulatory genetic elements called super-enhancers, which we can detect with novel whole genome technologies.
This project aims to map the super-enhancer landscape in human HGSOC tissue samples, and well as normal cells-of-origin, and tumor cell line models. This approach will yield fundamental insights into the mechanisms by which normal cells transform into ovarian cancer cells, and reveal the genes that maintain the oncogenic state in this disease.
Genetic dependencies are genes required for survival or growth of tumor cells, and represent attractive targets for cancer drug development. Super-enhancers are known to mark genes that are dependencies in several tumors. In cancers such as ependymoma and medulloblastoma, super-enhancer analysis has already pointed to novel therapeutic opportunities. Thus, by mapping the super-enhancer landscape of HGSOC, we will uncover putative therapeutic targets, which can be rapidly feed clinical trial development for patients.
This grant is made possible in part by a generous donation from Rock ‘N Run.
Dr. Isaac Klein is a Medical Oncology Fellow and Postdoctoral Fellow at the Dana-Farber Cancer Institute of Harvard University and the Whitehead Institute of the Massachusetts Institute of Technology, in the laboratory of Dr. Richard Young. His research focuses on understanding the role of transcriptional dysregulation in malignancy, and how this might reveal opportunities for novel therapies.
Dr. Klein was an undergraduate at Cornell University in the Department of Biological and Agricultural Engineering. He completed a PhD in Biology at The Rockefeller University and an MD at the Weill Cornell Medical College. He completed Internal Medicine residency training at the Brigham and Women’s Hospital of Harvard University, serving as Chief Medical Resident at the West Roxbury Veteran’s Affairs Hospital. He is a recipient of a Rockefeller Hearst Fellowship, a Cancer Research Institute Fellowship, The Franklyn Ellenbogen Prize in Hematology and Oncology, and a Keystone Scholarship.