Dokument: Preclinical evaluation of HDAC inhibitors for epigenetic therapy of primary brain tumors
| Titel: | Preclinical evaluation of HDAC inhibitors for epigenetic therapy of primary brain tumors | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=52111 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20220420-093855-9 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Marquardt, Viktoria [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Kurz, Thomas [Gutachter] PD Dr. med. Felsberg, Jörg [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 540 Chemie | |||||||
| Beschreibung: | Advances in next generation genomic technologies have yielded remarkable progress in our understanding of the biology underlying brain tumors and helped to identify distinct molecular characteristics for the different entities. As further layers of heterogeneity within the entities are being unraveled, genomic sequencing and copy number profiling also identified frequent alterations of chromatin modifiers, suggesting that epigenetic deregulation is an important driver of oncogenic transformation. Epigenetic modifications, such as DNA methylation or histone acetylation, and the information they convey are essential for the regulation of all DNA-based processes including transcription, replication and repair. Abnormal expression patterns or genomic alterations in chromatin modulators can therefore have profound impact on cell identity and lead to the induction and progression of cancers. To improve survival of high-risk patients and reduce the significant long-term sequelae associated with conventional chemotherapeutic treatment, implementation of rational therapies are highly warranted. Moreover, reversing aberrant epigenetic signature in cancer using targeted inhibitors has increasingly gained attention in the last decades, as exemplified by the clinical approval of inhibitors of DNA methyltransferases (DNMT) and histone deacetylase (HDAC) for the treatment of various cancers.
To accelerate and facilitate the discovery of novel inhibitors with translational potential, we established an institutional drug-screening pipeline that allows for the simultaneous evaluation of hundreds of compounds in large cell line cohorts. The optimized workflow was streamlined by semi-automated dispensing of inhibitors and cell lines, providing high accuracy and reproducibility. Our unique panel of cell lines, derived from the most common malignant brain tumor entities of infancy, childhood and adulthood, was screened with an institutional HDAC inhibitor (HDACi) library. The library is composed of clinically tested and approved HDACi as well as a unique compound collection synthesized in-house. Evaluation of over 250 inhibitors in 34 cell lines provided notable insights regarding the susceptibilities of distinct entities and subtypes for inhibition of HDACs. The cross-entity comparison showed that MYC amplified Group 3 medulloblastoma are particularly sensitive towards HDAC inhibition and that the clinically tested HDAC 1-3 selective inhibitor CI 994 was the most significantly active inhibitor among the commercially available compounds. Further in vitro evaluation demonstrated induction of apoptosis and decreased MYC expression levels following CI 994 treatment of MYC driven medulloblastoma cells. Confirming our screening approach, we demonstrated significantly extended survival in two orthotopic xenograft mouse models of MYC-driven medulloblastoma. CI-994 treatment decreased not only tumor growth at the primary site, but more noteworthy, elicited significant activity against metastatic dissemination. RNA sequencing results of treated cells identified significant upregulation of NFκB pathway genes in CI-994 treated cells. We further utilized the established screening workflow for large-scale synergy interaction studies. By screening CI 994 in combination with a library of 199 clinically established chemotherapeutics as well as targeted agents currently under clinical evaluation, we could identify several promising interactions. Amongst already established combination partners for HDACi such as DNA methyltransferases or proteasome inhibitors, we also showed that the NFκB pathway inhibitor bardoxolone methyl acts highly synergistic in combination with CI-994. Corroborating our RNA sequencing data, the results from the synergy screening further underlined that the NFκB pathway is activated upon CI-994 treatment and is functionally relevant. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie » Pharmazeutische und Medizinische Chemie | |||||||
| Dokument erstellt am: | 20.04.2022 | |||||||
| Dateien geändert am: | 20.04.2022 | |||||||
| Promotionsantrag am: | 02.10.2019 | |||||||
| Datum der Promotion: | 12.12.2019 |
