Overcoming off-target changes in gene expression by targeting epigenetic enzyme inhibitors to oncogenes using LNA-drug bioconjugates
| dc.contributor.author | Lillico, Ryan | |
| dc.contributor.examiningcommittee | Tranmer, Geoff (Pharmacy) McKenna, Sean (Chemistry) Doschak, Michael (University of Alberta) | en_US |
| dc.contributor.supervisor | Lakowski, Ted (Pharmacy) | en_US |
| dc.date.accessioned | 2019-02-25T14:37:32Z | |
| dc.date.available | 2019-02-25T14:37:32Z | |
| dc.date.issued | 2019 | en_US |
| dc.date.submitted | 2019-02-17T21:45:05Z | en |
| dc.date.submitted | 2019-02-22T15:44:05Z | en |
| dc.degree.discipline | Pharmacy | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Inhibition of epigenetic drug targets is growing into a powerful tool to regulate gene expression for the treatment of many diseases. This has become the new frontier of candidate therapies for cancer treatment. However, epigenetic enzymes, such as histone modifiers, are critical regulators of gene expression throughout the genome and there is currently no way to target an inhibitor to a particular diseased gene. Here we show the histone deacetylase (HDAC) inhibitors vorinostat, entinostat and mocetinostat (current and candidate treatments for lymphoma) inhibit the expression of lysine demethylases, and in the case of mocetinostat, results in the off-target increase of total histone lysine methylation. We identified that inhibition of key regulatory elements results in the alteration of other histone-modifiers that results in unpredictable, cascading changes in gene expression. We also show that in addition to HDAC, inhibitors of the disruptor of telomere silencing 1-like (DOT1L) and the lysine specific demethylase 1 (LSD1) (candidate treatments for leukemia) lead to similar off-target and unanticipated effects on the expression of histone-modifying enzymes, depending on cell type and dose. These approaches in epigenetic therapy often lead to the discontinuation of treatment due to the nature of their off-target effects. Therefore these inhibitors should be targeted to a particular diseased gene. We propose this may be achieved by conjugating the inhibitors to single stranded locked nucleic acid (LNA) oligonucleotide mixmers that are complementary to the genes those inhibitors are intended to target. Our experiments show that such LNA-drug conjugates increase the potency of DOT1L inhibitors by 16-fold. | en_US |
| dc.description.note | May 2019 | en_US |
| dc.identifier.citation | Lillico, Ryan et al. "Inhibitors of enzymes catalyzing modifications to histone lysine residues: structure, function and activity." Future medicinal chemistry 8 (2016): 879-897. | en_US |
| dc.identifier.citation | Lillico, Ryan et al. "HDAC inhibitors induce global changes in histone lysine and arginine methylation and alter expression of lysine demethylases." Journal of Proteomics 133 (2016): 125-133. | en_US |
| dc.identifier.citation | Lillico, Ryan et al. "Selective DOT1L, LSD1 and HDAC Class I inhibitors reduce HOXA9 expression in MLL-AF9 rearranged leukemia cells, but dysregulate the expression of many histone modifying enzymes." Journal of Proteome Research 17, 8 (2018): 2657-2667 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/33761 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | Epigenetics | en_US |
| dc.subject | Mixed Lineage Leukemia | en_US |
| dc.subject | HDAC | en_US |
| dc.subject | DOT1L | en_US |
| dc.subject | LSD1 | en_US |
| dc.title | Overcoming off-target changes in gene expression by targeting epigenetic enzyme inhibitors to oncogenes using LNA-drug bioconjugates | en_US |
| dc.type | doctoral thesis | en_US |