Examining a new class of dual CDC7/CDK9 inhibitors, mechanisms of proliferation, and proliferation-based stratification in myeloma
Coyne, Mark Robert
MetadataShow full item record
This item's downloads: 242 (view details)
A key feature of progressive myeloma is a relative increase in proliferation. The DBF4-dependent kinase (DDK), cell division cycle 7 (CDC7), is an essential kinase for initiation of DNA replication. This thesis assesses the activity of the prototype CDC7 inhibitor PHA-767491 and its bioavailable related compound, NMS-354, in pre-clinical models of myeloma. Both such inhibitors are characterised as dual CDC7/CDK9 inhibitors. The thesis finds first that PHA-767491 and NMS-354 demonstrate efficacy in pre-clinical cell-based myeloma and stem cell models. Secondly, CDC7/CDK9 inhibition is found to be additive to melphalan, bortezomib, and doxorubicin in myeloma cell lines. The combination of p38 MAPK and CDC7/CDK9 inhibitors is, unexpectedly, potently synergistic. CDC7/CDK9 inhibition activates MK2, a downstream target of the p38 MAPK pathway. However, thirdly, preliminary experiments did not reveal activity of NMS-354 in the Vk*MYC myeloma mouse models. Fourthly, DBF4 is found to be the main regulator of CDC7 in malignant and non-malignant plasma cells. DBF4 overexpression predicts an inferior overall survival and time to progression in newly diagnosed myeloma patients, but fails to reach independence from the gene-expression-based proliferation index on multivariate analysis. Dual staining with CD138, a plasma cell marker, and pMCM2 proves to be more predictive of plasma cell labeling index than the MIB index and gene expression-based proliferation indices. Finally, this thesis finds that the G2/M DNA damage checkpoint is the most important canonical pathway enriched in patients with a high proliferation index across TC myeloma groups. Through the analysis of these various elements, this thesis examines the role of proliferation as a therapeutic strategy as well as a stratifier in myeloma, through examination of the DDK, CDC7.
This item is available under the Attribution-NonCommercial-NoDerivs 3.0 Ireland. No item may be reproduced for commercial purposes. Please refer to the publisher's URL where this is made available, or to notes contained in the item itself. Other terms may apply.
The following license files are associated with this item: