The key to developing new cancer therapeutics is to find differences in how cancer and normal cells function in order to selectively target cancer-driving pathways. Heterozygous somatic mutations in components of the RNA splicing machinery have been discovered in some cancers such as acute myeloid leukemia, lung adenocarcinoma, and uveal melanoma. RNA splicing is essential for the survival of higher eukaryotes, and mutation of the RNA splicing machinery can lead to aberrantly spliced RNA isoforms that either take on novel functions or are degraded through the nonsense-mediated decay (NMD) pathway. Mutations in RNA splicing factors may also create haploinsufficiency for normal splicing. We hope to be able to harness this vulnerability in the RNA splicing machinery in cancer cells to develop targeted therapeutics. I advanced the construction of Luciferase-based minigene constructs that model the process of pre-mRNA splicing, with the goal of generating splicing reporter cell lines that will help in analyzing the effects of drugs that inhibit the RNA splicing machinery. As a complementary approach, I investigated the effects of splicing modulators on the splicing of endogenous genes. These assays will lay the foundation for future high throughput drug screens to help identify RNA splicing inhibitors that can selectively kill cancer cells with minimal toxicity on normal cells. Such compounds may modulate pathogenic alternative splicing in cancer and have potential as novel cancer therapeutics.
PROJECT: Modeling pathogenic alternative splicing in cancer
My summer at the Broad was such an enriching experience to me as an aspiring scientist. This experience showed me what it means to persevere and think critically. I was pleasantly surprised at the relevance of the research I was doing with regards to human disease, the emphasis on collaboration and learning, and the amount of support that was provided by both my mentor and the SRPG staff. I was surrounded by people who were on my side and willing to do whatever it took to help me improve as a scientist.