Ovarian cancer is the fifth leading cause of cancer-related deaths in women. There are about 20,000 new cases per year and only 46% of those women survive five years. Despite aggressive treatments of surgical resection followed by highly toxic chemotherapies and radiation, ovarian cancer outcomes have remained dismal due to lack of early detection and lack of availability of targeted treatments. Recent research has revealed that ovarian cancer subtypes have diverse genetic backgrounds and suggest a need to develop specialized therapeutic strategies for specific subtypes. Several ovarian cancer subtypes have high mutation frequencies in SWI/SNF (switch/sucrose non-fermentable) complex members. The SWI/SNF complex was first discovered in yeast for its involvement in mating type switching and sugar metabolism. The SWI/SNF complex is a chromatin remodeler whose job is to properly space and place nucleosomes, the protein spools for DNA, throughout the genome. Proper placement of these nucleosome spools is critical for global regulation of gene expression and development. Over 98% of Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT) tumors bear mutations in the SMARCA4 gene, which encodes a catalytic SWI/SNF complex member. SCCOHT is an especially aggressive form of ovarian cancer occurring in young women (average onset age of 24) with no stage IV patients surviving beyond 13 months. The genetic uniformity of SCCOHT provides a unique model to understand how disruption of SWI/SNF affects cancer biology in order to design effective treatment strategies for SWI/SNF-mutant ovarian cancers. I have characterized how the molecular interactions with SWI/SNF and other proteins are changed in SCCOHT. These data show that RNA processing, an important step in gene regulation, may be dysregulated in SCCOHT. My study will further characterize the interactions with SWI/SNF and RNA to determine how RNA processing and other RNA-dependent SWI/SNF functions are changed in SCCOHT. Importantly, altered RNA processing can result in tumor-specific antigens, which signal foreign entities to immune cells. Understanding how SCCOHT tumors might make antigens will help us choose treatments that would utilize the patient’s immune system to attack cancer cells. The results of this study will inform what types of immune therapies might be effective for SCCOHT patients. As SWI/SNF is frequently mutated in many cancer types including other ovarian cancer subtypes, these results will extend to other SWI/SNF-mutant cancers.
This grant was made possible by a generous donation by Phil and Judy Messing, in memory of Carol Messing.
Dr. Elizabeth Raupach is a postdoctoral fellow in the laboratory of Dr. Jeffrey Trent, TGen President and Research Director, where she leads molecular biology research to understand how altered chromatin landscapes drive tumorigenesis.
Dr. Raupach earned a Magna Cum Laude Bachelor of Science degree in Biochemistry and Molecular Biology from the University of Wisconsin—Eau Claire, where she studied organic synthetic chemistry in the laboratory of Dr. David Lewis. As a Bachelor’s student, Dr. Raupach was awarded the Chair’s Award for Outstanding Student Achievement, the CRC Freshman of the Year Award from the Department of Chemistry at the University of Wisconsin—Eau Claire, and a Hershey’s Bright Futures Scholarship from The Hershey Company.
Dr. Raupach studied RNA biology, transcription elongation, and chromatin regulation under the guidance of Dr. Karen Arndt during her doctoral training at the University of Pittsburgh. Her thesis work illuminated a mechanism of gene regulation in Saccharomyces cerevisiae, in which transcription of an unstable non-coding RNA positively regulates expression of a neighboring protein-coding gene by altering histone post-translational modifications across its promoter. During her doctoral studies, Dr. Raupach received a graduate student fellowship from the Dietrich College of Arts and Sciences and the Stanton C. Crawford Award for Excellence as a Graduate Student Teaching Assistant from the Department of Biological Sciences at the University of Pittsburgh.
In her current research, Dr. Raupach is studying the molecular alterations associated with loss of function mutations in subunits of the SWI/SNF chromatin remodeling complex observed in ovarian cancers. Dr. Raupach has characterized the altered SWI/SNF complex integrity and protein-protein interaction networks which illuminated a connection between SWI/SNF subunit mutations and altered RNA processing. Altered RNA processing could be a source of antigens in low mutation burden tumors, which may sensitize tumors to immune therapies and would suggest their use in ovarian cancer patients bearing SWI/SNF subunit mutations.
With the support of the Ovarian Cancer Research Alliance, Dr. Raupach will further characterize these molecular events in an ovarian cancer subtype that is nearly universally driven by loss of function mutations in the catalytic subunit of the SWI/SNF complex.