Mechanisms of Medulloblastoma Dissemination and Novel Targeted Therapies
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1254
Medulloblastoma, Recurrence, MYC, SOX9, FBW7, Treatment, BET bromodomains, Cyclin-dependent kinases
Research subject Oncology
IdentifiersURN: urn:nbn:se:uu:diva-300907ISBN: 978-91-554-9692-0OAI: oai:DiVA.org:uu-300907DiVA: diva2:971666
2016-11-04, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Roussel, Martine F., Professor
Swartling, Fredrik, Assistant Professor
List of papers