Online Archive of University of Virginia Scholarship
RNA Polymerase I Inhibition in Ovarian Cancer310 views
Author
Cornelison, John, Experimental Pathology - School of Medicine, University of Virginia
Advisors
Landen, Charles, MD-OBGY Gyn Oncology UPG-MD-OBGY Gyn Oncology, University of Virginia
Abstract
Ovarian cancer is the fifth leading cancer killer of women and little progress has been made in achieving better outcomes. A primary reason for its lethality is acquired chemotherapy resistance. We sought to model chemoresistance in patient derived xenografts (PDX) in mice that are treated with standard of care (SOC) chemotherapy. After transcriptomic profiling of treated PDX we identified the ribosome biogenesis system as upregulated in tumors surviving treatment. Our primary hypothesis is that chemoresistant ovarian cancer requires enhanced ribosome RNA transcription to survive chemotherapy, and pharmacologic inhibition of ribogenesis will kill chemoresistant disease. Our results indicated that ovarian cancer is sensitive to RNA polymerase I inhibition with CX-5461, that paclitaxel resistant cells may be hypersensitive to it, and that CX-5461 induces the DNA damage response. During the course of these experiments we observed an unreported effect of CX-5461 treatment. Cytosolic DNA began accumulating ~1 hour after treatment. The cytosolic DNA sensing system activated and led to a type I interferon response. Agonists to the cytosolic DNA sensing system are widely sought after as a possible means of increasing response rates to checkpoint inhibitors.
Cornelison, John. RNA Polymerase I Inhibition in Ovarian Cancer. University of Virginia, Experimental Pathology - School of Medicine, PHD (Doctor of Philosophy), 2020-10-16, https://doi.org/10.18130/v3-ejqz-6e19.
