2020 Theses Doctoral

Discovery of New Cancer Therapeutic Contexts for Ferroptosis Inducers and other Small-Molecule Drugs

Ye, Ling Feng

Small molecule drugs are powerful tools with many applications, ranging from discovering fundamental biological mechanisms to targeting and treating molecular causes of human disease. However, due to the large diversity of biological systems, it is important to identify the contexts in which a particular compound might be most effectively used. In this thesis, we explore two different, but related, problems that aim to further drug discovery by identifying the best disease models for a given small molecule. The first part of this thesis focuses on exploring the use of small-molecule ferroptosis inducers to potentiate radiation-induced cell death. Using a series of cell-based and biochemical assays, RT-qPCR, immunofluorescence, flow cytometry, and untargeted lipidomics, we discovered that IKE and RSL3 sensitize sarcoma, glioma, and lung cancer cells to radiation, and that ferroptosis is a previously unknown form of radiation-induced cancer cell death. Using patient-derived xenografts of lung adenocarcinoma and organotypic glioma slices, we demonstrate that ferroptosis induced by a combination of radiation and small molecules can be used to suppress tumor progression in human models of disease. The second part of this thesis aims to use human glioblastoma neurosphere cultures to correlate drug sensitivity with RNA expression. Using RNA-seq and high throughput drug screening, we demonstrate that differential sensitivity to MDM2 and EGFR inhibitors can be predicted from gene expression and mutational status in this model of glioblastoma.