Identification of Novel Therapeutic Strategies Against MLL-rearranged Acute Lymphoblastic Leukemia in Infants
Year: 2019
Type: dissertation
Abstract: Introduction 1 patient is still a time-consuming process, especially considering the fact that these drugs need to be safe and efficacious in adults before the transition can be made to pediatric application.Awaiting results from clinical investigation of these previously identified therapeutics, this thesis describes the investigation of new therapeutic candidates, predominately FDA-approved and off-patent drugs, in order to expedite the implementation of potent agents into current therapeutic regimens for MLLrearranged infant ALL. Outline of this thesisChapter 2 describes a drug repurposing approach through screening of mainly FDAapproved and off-patent drugs on different MLL-rearranged infant ALL and BCP-ALL cell line models.This led to the identification of topoisomerase I inhibitors, especially 7-ethyl-10-hydroxycampthotecin (SN-38), as potent inhibitors of MLLrearranged infant ALL cells in vitro.Additionally, the efficacy of the SN-38 prodrug irinotecan was investigated in vivo using xenograft mouse models of MLLrearranged infant ALL.In chapter 3, we report the investigation of inhibitors against MLL-rearranged ALL cells harboring additional RAS mutations.Hereto, different (approved) inhibitors of RAS-pathway components were tested on MLL-rearranged cell line models, as well as primary patient material.Among all inhibitors tested in this study, MEK inhibitors showed the most promising results.Moreover, since RAS mutations are associated with glucocorticoid resistance, we investigated the effect of MEK inhibition on the response of MLL-rearranged ALL cells to the glucocorticoid prednisolone, and observed glucocorticoid-sensitizing effects.Furthermore, chapter 4 reports the in vivo evaluation of trametinib, the most potent MEK inhibitor as found in chapter 3, in a xenograft mouse model of RAS mutant MLL-rearranged infant ALL.Since MLL-rearranged infant ALL is characterized by aberrant histone methylation and DNA methylation, we performed drug screens using two drug libraries consisting of epigenetic drugs in chapter 5. S-adenosylhomocysteine hydrolase inhibitors potently inhibited MLL-rearranged infant ALL in vitro.Additionally, we investigated the mechanism of action of these inhibitors, while also assessing efficacy in an MLLrearranged infant ALL xenograft mouse model.Finally, the results described in this thesis are discussed and summarized in chapter 6, and chapter 7 provides a layman's summary in Dutch.
Author: Mark Kerstjens
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2969659750