Novel functions of MDMX and innovative therapeutic strategies for melanoma

Leiden Repository

Novel functions of MDMX and innovative therapeutic strategies for melanoma

Type: Doctoral Thesis
Title: Novel functions of MDMX and innovative therapeutic strategies for melanoma
Author: Heijkants, R.C.
Issue Date: 2018-10-18
Keywords: Molecular cell biology
Uveal melanoma
Melanoma
p53
MDMX
Synergism
Abstract: The focus of this thesis is uveal melanoma (UM) which, once metastasized, is lethal due to lack of effective treatment options. To repress p53 activity approximately 65% of UM tumors express high levels of the p53 inhibitory proteins MDMX or MDM2. The aim of this thesis is to unravel the oncogenic function of MDMX and provide new treatment options for patients with metastasized UM. Chapter 2 describes the regulation of the transcriptome by MDMX in UM and proposes novel p53-independent effects of MDMX, i.e. FOXO inhibition. In chapter 3 the opportunities of a combined targeting of two common signaling pathways as therapeutic intervention for metastasized UM patients is investigated. Genetic interference with either MDMX or PKC δ expression or activity showed that beneficial effects can already be achieved by a more specific targeting, which is presumable less toxic to the patient. In chapter 4 it is described, opposed to what has been reported before, that enhancer of zeste homolog 2 (EZH2) inhibition poses a valuable novel therapeutic invention for UM. In chapter 5 it is shown that combining two clinically approved drugs, Quisinostat and Flavopiridol, could serve as an effective therapeutic intervention for UM patients.
Promotor: Supervisor: Dijke P. ten Co-Supervisor: Jochemsen A.G.
Faculty: Faculty of Medicine, Leiden University Medical Center (LUMC)
University: Leiden University
Uri: urn:isbn:9789493019508
Handle: http://hdl.handle.net/1887/66268
 

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application/pdf Title Pages_Contents 773.9Kb View/Open
application/pdf Chapter 1 1.405Mb Under embargo until 2020-04-18
application/pdf Chapter 2 4.600Mb Under embargo until 2020-04-18
application/pdf Chapter 3 3.297Mb View/Open Full text at publisher site
application/pdf Chapter 4 2.408Mb Under embargo until 2020-04-18
application/pdf Chapter 5 3.871Mb View/Open Full text at publisher site
application/pdf Chapter 6 909.9Kb View/Open
application/pdf Summary in Dutch 747.6Kb View/Open
application/pdf Curriculum Vitae_Publications_Acknowledgements 761.6Kb View/Open
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