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|Ref Type||Journal Article|
|Authors||Henssen A, Thor T, Odersky A, Heukamp L, El-Hindy N, Beckers A, Speleman F, Althoff K, Schafers S, Schramm A, Sure U, Fleischhack G, Eggert A, Schulte JH|
|Title||BET bromodomain protein inhibition is a therapeutic option for medulloblastoma.|
|Abstract Text||Medulloblastoma is the most common malignant brain tumor of childhood, and represents a significant clinical challenge in pediatric oncology, since overall survival currently remains under 70%. Patients with tumors overexpressing MYC or harboring a MYC oncogene amplification have an extremely poor prognosis. Pharmacologically inhibiting MYC expression may, thus, have clinical utility given its pathogenetic role in medulloblastoma. Recent studies using the selective small molecule BET inhibitor, JQ1, have identified BET bromodomain proteins, especially BRD4, as epigenetic regulatory factors for MYC and its targets. Targeting MYC expression by BET inhibition resulted in antitumoral effects in various cancers. Our aim here was to evaluate the efficacy of JQ1 against preclinical models for high-risk MYC-driven medulloblastoma. Treatment of medulloblastoma cell lines with JQ1 significantly reduced cell proliferation and preferentially induced apoptosis in cells expressing high levels of MYC. JQ1 treatment of medulloblastoma cell lines downregulated MYC expression and resulted in a transcriptional deregulation of MYC targets, and also significantly altered expression of genes involved in cell cycle progression and p53 signalling. JQ1 treatment prolonged the survival of mice harboring medulloblastoma xenografts and reduced the tumor burden in these mice. Our preclinical data provide evidence to pursue testing BET inhibitors, such as JQ1, as molecular targeted therapeutic options for patients with high-risk medulloblastomas overexpressing MYC or harboring MYC amplifications.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|JQ1||JQ-1||BET Inhibitor (Pan) 32||JQ1 is a BET bromodomain inhibitor with greatest specificity towards BRD4, resulting in decreased Myc expression, increased cell death, reduced macrophage immunosuppression, and inhibition of tumor growth (PMID: 24231268, PMID: 31018997, PMID: 30906568, PMID: 32800944).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|TP53 wild-type||medulloblastoma||sensitive||JQ1||Preclinical||Actionable||In a preclinical study, medulloblastoma cell lines with TP53 mutations had significantly less sensitivity to the BET inhibitor, JQ1, than cell lines carrying wild-type TP53 (PMID: 24231268).||24231268|
|TP53 mutant||medulloblastoma||decreased response||JQ1||Preclinical||Actionable||In a preclinical study, medulloblastoma cell lines with TP53 mutations had significantly less sensitivity to the BET inhibitor, JQ1, than cell lines carrying wild-type TP53 (PMID: 24231268).||24231268|