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From Genes to Therapy: Modeling and Novel Therapeutic Strategies for Brain Tumors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. (Fredrik Swartling)ORCID iD: 0000-0001-5825-5151
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Medulloblastoma is the most common malignant pediatric brain tumor and is molecularly divided into four subgroups – WNT, SHH, Group 3 and Group 4. Two thirds of medulloblastoma patients survive, but survivors often suffer from severe, lifelong side-effects. The MYCN oncogene is deregulated in many medulloblastoma patients. Glioblastoma is the most common malignant brain tumor in adults, with a median survival of about one year. Glioblastoma is a highly heterogeneous tumor where targeted therapy has, so far, not been successful and most glioblastoma patients unfortunately die.

In our first study we developed three novel humanized models of MYCN-driven SHH medulloblastoma. Histologically and molecularly these models closely resembled the infant class of SHH tumors. Further, we identified a set of clinically relevant genes that had prognostic significance among patients. mTOR signaling pathway was identified as a major contributor to invasion and dissemination, and we showed that mTOR specific inhibition suppressed migration and viability in vitro.

In the second study we performed a forward genetic screen of retrovirally-induced murine PDGFB-driven gliomas and identified more than fifty candidate cancer-causing genes, of which many were mutated or deregulated in glioblastoma. One of the genes identified in this screen was PPFIBP1, found to be differentially expressed from obstructive retroviral integrations in PDGFB-driven glioma clones. Lower PPFIBP1 expression significantly decreased survival of mice and was found to be suppressed in glioblastoma patients. We propose PPFIBP1 to be a novel tumor suppressor gene that contributes to glioblastoma development.

In the last study we used a panel of 19 patient-derived glioblastoma cell lines and identified a characteristic expression signature that predicts sensitivity to BET inhibition. BET inhibition resulted in apoptosis and senescence, cell cycle arrest and modulation of DNA damage response. The inhibitory effects of BET inhibition were further enhanced in combination with temozolomide, suggesting a promising future therapy for distinct subgroups of glioblastoma patients.

This thesis addresses novel molecular findings in medulloblastoma and glioblastoma development, presents clinically relevant brain tumor models, and promising therapeutic approaches that can be used in future clinical trials in malignant pediatric and adult brain tumors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. , p. 62
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1409
Keyword [en]
Medulloblastoma, Glioblastoma, MYCN, PDGF, Cancer Therapy, BET bromodomains, Temozolomide
National Category
Basic Medicine
Research subject
Medical Science; Oncology
Identifiers
URN: urn:nbn:se:uu:diva-334662ISBN: 978-91-513-0183-9 (print)OAI: oai:DiVA.org:uu-334662DiVA, id: diva2:1163772
Public defence
2018-02-02, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2018-01-10 Created: 2017-12-08 Last updated: 2018-03-07
List of papers
1. MYCN Drives Disparate Medulloblastoma from Human Embryonic and iPSC-Derived Stem Cells
Open this publication in new window or tab >>MYCN Drives Disparate Medulloblastoma from Human Embryonic and iPSC-Derived Stem Cells
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(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-334659 (URN)
Available from: 2017-11-25 Created: 2017-11-25 Last updated: 2018-01-13
2. An RCAS/tva Forward Genetic Screen Identifies Novel Candidate Genes Involved in Gliomagenesis
Open this publication in new window or tab >>An RCAS/tva Forward Genetic Screen Identifies Novel Candidate Genes Involved in Gliomagenesis
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(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-334660 (URN)
Available from: 2017-11-25 Created: 2017-11-25 Last updated: 2018-01-13
3. BET Inhibition in Combination with Temozolomide Targets Human Glioblastoma Cells
Open this publication in new window or tab >>BET Inhibition in Combination with Temozolomide Targets Human Glioblastoma Cells
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(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-334661 (URN)
Available from: 2017-11-25 Created: 2017-11-25 Last updated: 2018-01-13

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