Identification of anti-resorptive and anti-cancer activities of epigenetic inhibitors

Thesis

Multiple myeloma is a plasma cell malignancy and develops in the bone marrow. The myeloma bone disease is present in the majority of the myeloma patients and is characterised by the excessive numbers and increased resorptive functions of osteoclasts. In order to identify novel targets controlling both osteoclastogenesis and myeloma cell growth, a library of epigenetic compounds was screened in an osteoclast differentiation assay and myeloma cell viability assay. Some compound classes, such as BET bromodomain inhibitors and HDAC inhibitors, showed inhibitory effects on both osteoclast differentiation and myeloma cell proliferation, suggesting that chromatin modifying reagents are possible therapeutic targets in multiple myeloma treatment. To rapidly screen for anti-osteoclast effects, an osteoclast RANKL gene card was successfully developed and applied to selected inhibitors in osteoclast assays. Moreover, the transcriptomic analysis was used to investigate the underlying mechanisms of selected epigenetic compounds in myeloma cells, and we found that cell cycle related pathways have been regulated by several inhibitors. Furthermore, an antibody panel for CyTOF (Mass cytometry) has been developed to characterise the bone marrow microenvironment of myeloma patients, and the CyTOF experiments demonstrated that GSK-J4 and rocilinostat activate the apoptosis marker caspase3 only in myeloma cells without affecting other cell populations. GSK-J4, an inhibitor for KDM5 and KDM6, was shown to upregulate the metallothioneins and induce the ATF4-mediated stress response in myeloma cells, whereas the KDM5B inhibitors causes cell cycle arrest rather than apoptosis.

Authors: Wu, N

• DOI: 10.5287/ora-rjgroxdeq
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford