Elucidating the Role of R-loops as Modulators of Glioblastoma Aggression

Glioblastoma (GBM) is a form of brain cancer that affects 12,000 adults in the US every year. Treatment usually involves surgical resection, followed by radiation and chemotherapy. Unfortunately, despite such invasive treatment, the average survival is only a year after diagnosis. This poor prognosis seems to be due to GBM’s inherent aggressiveness, the reason for which remains largely unknown. To determine which genes are responsible for this aggressiveness, our lab performed a genome-wide screen in GBM cells. From this screen, we identified one gene in particular, THOC1, that was found to drive this aggressiveness. Although previously unstudied in GBM, THOC1 is known to prevent deadly structures called R-loops from forming on DNA. We hypothesize that THOC1 may be driving GBM aggression by preventing these harmful R-loops from forming specifically on the ends of DNA. Since the ends of DNA, called telomeres, need to be especially protected for cancer to be aggressive, targeting THOC1’s protective force could be a way to kill GBM cells. In this study, we will 1) investigate the link between THOC1 and R-loops on telomeres, and 2) assess the efficacy of the drug luteolin, a THOC1 inhibitor, which may be able to increase these toxic R-loops, kill GBM cells, and prolong survival. Overall, these findings will reveal crucial insight into an unknown mechanism of GBM aggression, providing a novel therapeutic approach for a disease desperately in need of effective therapies.