Enhancing chemotherapeutic responses in CNS malignancy through suppression of hyperactive DNA damage repair pathways
| dc.contributor.author | Mostafizar, Marina | |
| dc.contributor.examiningcommittee | Jackson, Michael (Pharmacology and Therapeutics) Gibson, Spencer (Biochemistry and Medical Genetics) | en_US |
| dc.contributor.supervisor | Katyal, Sachin (Pharmacology and Therapeutics) | en_US |
| dc.date.accessioned | 2018-08-16T13:15:46Z | |
| dc.date.available | 2018-08-16T13:15:46Z | |
| dc.date.issued | 2018-08-02 | en_US |
| dc.date.submitted | 2018-08-02T23:06:43Z | en |
| dc.date.submitted | 2018-08-15T17:39:04Z | en |
| dc.date.submitted | 2018-08-15T22:32:24Z | en |
| dc.degree.discipline | Pharmacology and Therapeutics | en_US |
| dc.degree.level | Master of Science (M.Sc.) | en_US |
| dc.description.abstract | Current methods to treat medulloblastoma (MB) and malignant glioma (MG) are highly intrusive with three-year survival. Recurrence is high due to chemoradio-resistance. We are targeting DNA repair pathways through inhibitors of DNA repair proteins; Poly (ADP-Ribose) Polymerase (PARP1i), DNA-dependent protein kinase (DNA-PKi) and Ataxia-Telangiectasia Mutated (ATMi) to sensitize tumours to DNA damaging agents. However, differing tumours have variable expression of these enzymes/repair pathway(s) activity, therefore; their identification and inhibition may enhance current treatment efficacy. High-throughput comet assay revealed enhanced drug-mediated tumour cell death in MB cell lines with TOPI+PARP1i with activation of specific repair pathways. Further, RNA-Seq analysis revealed PARP1 upregulated in DAOYMB and downregulated in D283; while BRCA1 downregulated in DAOYMB and upregulated in D283MB, suggesting defective Homologous recombination (HRR) pathway, hence synthetic lethality in MB cell line (DAOYMB). Therefore, I have identified unique DNA repair enzymes, which may mediate specific differential chemo-radioresistant phenotypes in MB. | en_US |
| dc.description.note | October 2018 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/33203 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | CNS malignancy | en_US |
| dc.subject | DNA repair pathways | en_US |
| dc.title | Enhancing chemotherapeutic responses in CNS malignancy through suppression of hyperactive DNA damage repair pathways | en_US |
| dc.type | master thesis | en_US |
| local.subject.manitoba | yes | en_US |