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BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma
Departments of Cancer Biology and Pediatric Neuro-Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Pediatric Hematology/Oncology, Boston Children's Hospital; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
Departments of Cancer Biology, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Pediatric Hematology/Oncology, Boston Children's Hospital; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
Vise andre og tillknytning
2014 (engelsk)Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 20, nr 4, s. 912-925Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Purpose:

MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma.

Experimental Design:

We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice.

Results:

Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index.

Conclusion:

JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.

sted, utgiver, år, opplag, sider
2014. Vol. 20, nr 4, s. 912-925
Emneord [en]
medulloblastoma, MYC
HSV kategori
Forskningsprogram
Onkologi
Identifikatorer
URN: urn:nbn:se:uu:diva-217950DOI: 10.1158/1078-0432.CCR-13-2281ISI: 000331875500015OAI: oai:DiVA.org:uu-217950DiVA, id: diva2:694314
Tilgjengelig fra: 2014-02-06 Laget: 2014-02-06 Sist oppdatert: 2017-12-06bibliografisk kontrollert
Inngår i avhandling
1. Mechanisms of Medulloblastoma Dissemination and Novel Targeted Therapies
Åpne denne publikasjonen i ny fane eller vindu >>Mechanisms of Medulloblastoma Dissemination and Novel Targeted Therapies
2016 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2016. s. 49
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1254
Emneord
Medulloblastoma, Recurrence, MYC, SOX9, FBW7, Treatment, BET bromodomains, Cyclin-dependent kinases
HSV kategori
Forskningsprogram
Onkologi
Identifikatorer
urn:nbn:se:uu:diva-300907 (URN)978-91-554-9692-0 (ISBN)
Disputas
2016-11-04, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:15 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2016-10-12 Laget: 2016-08-15 Sist oppdatert: 2018-01-10

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