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| 2. |
- Bolin, Sara, 1988-, et al.
(författare)
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Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma
- 2018
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Ingår i: Oncogene. - : Nature Publishing Group. - 0950-9232 .- 1476-5594. ; 37:21, s. 2850-2862
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Tidskriftsartikel (refereegranskat)abstract
- Medulloblastoma (MB) is the most common malignant brain tumor in children. MYC genes are frequently amplified and correlate with poor prognosis in MB. BET bromodomains recognize acetylated lysine residues and often promote and maintain MYC transcription. Certain cyclin-dependent kinases (CDKs) are further known to support MYC stabilization in tumor cells. In this report, MB cells were suppressed by combined targeting of MYC expression and MYC stabilization using BET bromodomain inhibition and CDK2 inhibition, respectively. Such combination treatment worked synergistically and caused cell cycle arrest as well as massive apoptosis. Immediate transcriptional changes from this combined MYC blockade were found using RNA-Seq profiling and showed remarkable similarities to changes in MYC target gene expression when MYCN was turned off with doxycycline in our MYCN-inducible animal model for Group 3 MB. In addition, the combination treatment significantly prolonged survival as compared to single-agent therapy in orthotopically transplanted human Group 3 MB with MYC amplifications. Our data suggest that dual inhibition of CDK2 and BET bromodomains can be a novel treatment approach for suppressing MYC-driven cancer.
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| 3. |
- Bolin, Sara
(författare)
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Mechanisms of Medulloblastoma Dissemination and Novel Targeted Therapies
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 4. |
- Cancer, Matko, et al.
(författare)
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BET and Aurora Kinase A inhibitors synergize against MYCN-positive human glioblastoma cells
- 2019
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Ingår i: Cell Death and Disease. - : NATURE PUBLISHING GROUP. - 2041-4889. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Patients usually undergo surgery followed by aggressive radio- and chemotherapy with the alkylating agent temozolomide (TMZ). Still, median survival is only 12-15 months after diagnosis. Many human cancers including GBMs demonstrate addiction to MYC transcription factor signaling and can become susceptible to inhibition of MYC downstream genes. JQ1 is an effective inhibitor of BET Bromodomains, a class of epigenetic readers regulating expression of downstream MYC targets. Here, we show that BET inhibition decreases viability of patient-derived GBM cell lines. We propose a distinct expression signature of MYCN-elevated GBM cells that correlates with significant sensitivity to BET inhibition. In tumors showing JQ1 sensitivity, we found enrichment of pathways regulating cell cycle, DNA damage response and repair. As DNA repair leads to acquired chemoresistance to TMZ, JQ1 treatment in combination with TMZ synergistically inhibited proliferation of MYCN-elevated cells. Bioinformatic analyses further showed that the expression of MYCN correlates with Aurora Kinase A levels and Aurora Kinase inhibitors indeed showed synergistic efficacy in combination with BET inhibition. Collectively, our data suggest that BET inhibitors could potentiate the efficacy of either TMZ or Aurora Kinase inhibitors in GBM treatment.
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| 5. |
- Hutter, Sonja, et al.
(författare)
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Modeling and Targeting MYC Genes in Childhood Brain Tumors
- 2017
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Ingår i: Genes. - : MDPI. - 2073-4425. ; 8:4
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Forskningsöversikt (refereegranskat)abstract
- Brain tumors are the second most common group of childhood cancers, accounting for about 20%-25% of all pediatric tumors. Deregulated expression of the MYC family of transcription factors, particularly c-MYC and MYCN genes, has been found in many of these neoplasms, and their expression levels are often correlated with poor prognosis. Elevated c-MYC/MYCN initiates and drives tumorigenesis in many in vivo model systems of pediatric brain tumors. Therefore, inhibition of their oncogenic function is an attractive therapeutic target. In this review, we explore the roles of MYC oncoproteins and their molecular targets during the formation, maintenance, and recurrence of childhood brain tumors. We also briefly summarize recent progress in the development of therapeutic approaches for pharmacological inhibition of MYC activity in these tumors.
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| 6. |
- Kahn, Suzana A., et al.
(författare)
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Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Medulloblastoma is the most common malignant brain tumor of childhood. Group 3 medulloblastoma, the most aggressive molecular subtype, frequently disseminates through the leptomeningeal cerebral spinal fluid (CSF) spaces in the brain and spinal cord. The mechanism of dissemination through the CSF remains poorly understood, and the molecular pathways involved in medulloblastoma metastasis and self-renewal are largely unknown. Here we show that NOTCH1 signaling pathway regulates both the initiation of metastasis and the self-renewal of medulloblastoma. We identify a mechanism in which NOTCH1 activates BMI1 through the activation of TWIST1. NOTCH1 expression and activity are directly related to medulloblastoma metastasis and decreased survival rate of tumor-bearing mice. Finally, medulloblastoma-bearing mice intrathecally treated with anti-NRR1, a NOTCH1 blocking antibody, present lower frequency of spinal metastasis and higher survival rate. These findings identify NOTCH1 as a pivotal driver of Group 3 medulloblastoma metastasis and self-renewal, supporting the development of therapies targeting this pathway.
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| 7. |
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| 8. |
- Nyhlén, Sara, et al.
(författare)
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Att studera lokalt beslutsfattande
- 2015
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Ingår i: Lokalt beslutsfattande. - Lund : Studentlitteratur AB. - 9789144105154 ; , s. 73-77
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 9. |
- Nyhlén, Sara, 1980-, et al.
(författare)
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When social inequality goes beyond the nation state : analyzing how Swedish municipalities handle vulnerable EU-migrants
- 2017
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Konferensbidrag (refereegranskat)abstract
- Since 2012 Sweden has faced a seemingly new situation with social inequality displaying itself as an increasing amount of homeless people making a living mainly as beggars in Swedish cities and towns. With the Swedish welfare state and the far reaching local autonomy this situation with social inequality is left to each municipality to decide upon how to handle. The situation is growing in complexity since the majority of the people in the precarious situation are so called “EU-migrants” which means that they are people traveling within EU seeking a better life trying to avoid poverty, unemployment and many times harassments and racism. In this study we have analyzed how it comes that this situation is handled differently by local authorities. Applying a most similar system design we look at how 7 municipalities within a region in the northern parts of Sweden handle the situation with social vulnerability. Given that the municipalities have the same political majority, are located in the same region and are ruled by the same national policies, we pose the question why is the outcome so different? The study shows how the local public officials and politicians are negotiating rights, citizenship and needs and how boundaries are drawn within the welfare state.
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| 10. |
- Olausson, Pär M., et al.
(författare)
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Lokalt beslutsfattande - en introduktion
- 2015
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Ingår i: Lokalt beslutsfattande. - Lund : Studentlitteratur AB. - 9789144105154 ; , s. 11-20
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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