Date of Award
Dinaciclib, Glioblastoma Multiforme
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Glioblastoma Multiforme (GBM) is a highly aggressive and devastating primary brain tumour with a prognosis of 12-15 months with standard of care treatments, which includes combinations of surgery, radiotherapy and chemotherapy. Aggressiveness, among other factors, is driven by the populations of brain tumour initiating cells, capable of self renewal, tumour recapitulation and high therapy resistance. Dinaciclib is a potent cyclin-dependent kinase (CDK) inhibitor (CKI) which inhibits GBM cell growth in vitro. This study confirmed the growth inhibition of GBM cells but also demonstrated enrichment for specific brain tumour initiating cell populations upon dinaciclib treatment. In the zebrafish (Danio rerio) model, dinaciclib showed less toxicity to the developing embryos than NU2058, another CKI with similar CDK targets. Embryos injected with U87 cells, a GBM cell line, were treated with dinaciclib and we demonstrated that there was a decrease in cell foci area after treatment with dinaciclib compared to the vehicle control. The breast cancer cells, MDA-MB-231, were also injected into zebrafish embryos to perform a comparative analysis of spatial trends in cell metastasis. Interestingly, there appears to be a preferential migration of injected cancer cells to the organ of cancer origin, with GBM cells migrating towards the brain and head and breast cancer cells migrating down the tail. In summary, we demonstrated that using a CKI simultaneously with a chemotherapy induces antagonistic effects in GBM cells, which demonstrates the importance of timing of drug administration in the clinic.
Stover, Mathew, "Dinaciclib Inhibits Glioblastoma Multiforme Cell Growth and Selects for a Brain Tumour Initiating Cell Population" (2019). Electronic Theses and Dissertations. 8151.