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Combined BET-bromodomain and CDK2 inhibition in MYC-driven medulloblastoma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. (Swartling)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. (Swartling)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. (Swartling)
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(English)Article in journal (Other academic) Submitted
Keyword [en]
MYC, BET Bromodomains, Cyclin dependent kinases, Treatment, Medulloblastoma
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-300906OAI: oai:DiVA.org:uu-300906DiVA: diva2:952849
Available from: 2016-08-15 Created: 2016-08-15 Last updated: 2016-10-11
In thesis
1. Mechanisms of Medulloblastoma Dissemination and Novel Targeted Therapies
Open this publication in new window or tab >>Mechanisms of Medulloblastoma Dissemination and Novel Targeted Therapies
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Medulloblastomas are the most frequent malignant childhood brain tumors, arising in the posterior fossa of children. The overall 5-year survival is 70%, although children often suffer severe long-term side effects from standard medical care. To improve progression-free survival and quality of life for these children, finding new therapeutic targets in medulloblastoma is imperative.

Medulloblastoma is divided in to four molecular subgroups (WNT, SHH, Group 3 and Group 4) based on key developmental pathways essential for the initiation and maintenance of tumor development. The MYC family of proto-oncogenes regulates cell proliferation and differentiation in normal brain. Aberrant expression of MYC proteins occurs commonly in medulloblastoma.

Our studies on Group 3 medulloblastoma identify the transcription factor SOX9 as a novel target for the E3 ubiquitin ligase FBW7, and show that increased stability of SOX9 confers an increased metastatic potential in medulloblastoma. Moreover, SOX9-positive cells drive distant recurrences in medulloblastoma when combining two regulatable TetON/OFF systems. MYCN depletion leads to increased SOX9 expression in Group 3 medulloblastoma cells, and the recurring tumor cells are more migratory in vitro and in vivo. Segueing to treatment of medulloblastoma, we show that BET bromodomain inhibition specifically targets MYC-amplified medulloblastoma cells by downregulating MYC and MYC-transcriptional targets, and that combining BET bromodomain- and cyclin-dependent kinase- inhibition improves survival in mice compared to single therapy. Combination treatment results in decreased MYC levels and increased apoptosis, and RNA-seq confirms upregulation of apoptotic markers along with downregulated MYC target genes in medulloblastoma cells.

This thesis addresses novel findings in transcription factor biology, recurrence and treatment in Group 3 medulloblastoma, the most malignant subgroup of the disease.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 49 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1254
Keyword
Medulloblastoma, Recurrence, MYC, SOX9, FBW7, Treatment, BET bromodomains, Cyclin-dependent kinases
National Category
Basic Medicine
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-300907 (URN)978-91-554-9692-0 (ISBN)
Public defence
2016-11-04, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-10-12 Created: 2016-08-15 Last updated: 2016-10-19

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