20 million new cases of cancer are diagnosed worldwide annually. Although prognosis for many cancers has improved over the last decade, treatment resistance and recurrence remain major challenges. Combining bioinformatic analyses and experimental work, new avenues to improve current therapies have been identified in three separate projects.
The first project addressed radiotherapy and chemotherapy efficacy in glioblastoma (GBM) patients. Studies suggested that the synthetic glucocorticoid dexamethasone (DEX), a potent anti-inflammatory prescribed to 70% of GBM patients, drives chemoresistance and radioresistance. By analysing RNA-sequencing data from DEX-treated GBM cells and comparing it with two non-resistance-inducing selective glucocorticoids, I revealed DEX’s role in promoting DNA repair and identified AZD7594 as a potentially safer alternative for GBM patients.
The second project explored a candidate for predicting patient response in recurrent GBM tumours. JARID2 is a cofactor for the Polycomb repressor complex 2 (PRC2), and genes that differentiate good from poor responders in recurrent GBM tumours are enriched in JARID2 binding sites. I characterised antibodies to detect JARID2 and used small molecule inhibitors downstream of JARID2 to determine if they altered the treatment response. While the inhibitors showed no significant effect, there are other candidates that could be investigated in the future.
The final project investigated treatment resistance in chronic myeloid leukaemia (CML). I analysed microarray data to identify kinase independent factors which may alter the treatment response. This revealed EZH2, the catalytic subunit of PRC2 that mediates transcriptional silencing through H3K27me3, and EZH1, the homologue of EZH2. I also identified PRAME, a transcriptional regulator. My experimental validation revealed that the dual suppression of EZH1 and EZH2 or decreased PRAME caused kinase-independent resistance to imatinib treatment in CML cell culture models.
Future work will investigate these potential new drugs or drug targets to determine if they can improve outcomes for patients with cancer.
