dc.contributor.advisor | Tansey, William P | |
dc.creator | Florian, Andrea C. | |
dc.date.accessioned | 2022-05-19T17:26:06Z | |
dc.date.created | 2022-05 | |
dc.date.issued | 2022-03-17 | |
dc.date.submitted | May 2022 | |
dc.identifier.uri | http://hdl.handle.net/1803/17389 | |
dc.description.abstract | Rhabdoid tumors (RT) are rare and deadly pediatric cancers driven by loss of SMARCB1, which encodes the SNF5 component of the SWI/SNF chromatin remodeler. Loss of SMARCB1 is associated with a complex set of phenotypic changes including vulnerability to inhibitors of protein synthesis and of the p53 ubiquitin-ligase HDM2. Recently, we discovered small molecule inhibitors of the "WIN" site of WDR5, which in MLL-rearranged leukemia cells decrease the expression of a set of genes linked to protein synthesis, inducing a translational choke and causing p53-dependent inhibition of proliferation. In this thesis, I characterize how WIN site inhibitors act in RT cells. As in leukemia cells, WIN site inhibition in RT cells causes the comprehensive displacement of WDR5 from chromatin, resulting in a decrease in protein synthesis gene expression. Unlike leukemia cells, however, the growth response of RT cells to WIN site blockade is independent of p53. Exploiting this observation, I demonstrate that dual treatment with WIN site and an HDM2 antagonist induce p53 and block RT cell proliferation in vitro. These data reveal a p53-independent action of WIN site inhibitors and forecast that future strategies to treat RT could be based on dual WDR5/HDM2 inhibition. | |
dc.format.mimetype | application/pdf | |
dc.language.iso | en | |
dc.subject | Rhabdoid tumors, pediatric cancer, WDR5, drug discovery | |
dc.title | EXPOSING THE POTENTIAL OF WDR5 WIN SITE INHIBITORS FOR THE TREATMENT OF RHABDOID TUMORS | |
dc.type | Thesis | |
dc.date.updated | 2022-05-19T17:26:07Z | |
dc.type.material | text | |
thesis.degree.name | PhD | |
thesis.degree.level | Doctoral | |
thesis.degree.discipline | Cell & Developmental Biology | |
thesis.degree.grantor | Vanderbilt University Graduate School | |
local.embargo.terms | 2023-05-01 | |
local.embargo.lift | 2023-05-01 | |
dc.creator.orcid | 0000-0003-2809-4662 | |
dc.contributor.committeeChair | Lee, Ethan | |