BET Bromodomain Inhibition ofMYC-Amplified Medulloblastoma

Abstract

Purpose MYC-amplified medulloblastomas are highly lethal tumors. 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 pharmacological inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and 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 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 down-regulation of MYC expression and confirmed inhibition of MYC-associated transcriptional targets. 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 survival of orthotopic xenograft models of MYC-amplified medulloblastoma (p<0.001). Xenografts harvested from mice after five doses of JQ1 had reduced 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.

The epigenetically active small chemical N-methyl pyrrolidone (NMP) prevents estrogen depletion induced osteoporosis

“…In many studies, treatment of cells with JQ1 results in cell viability reduction and in general inhibition of transcription [28][29][30]. In contrast, low affinity of NMP appears to be less toxic and more beneficial in our system.…”

An in-tumor genetic screen reveals that the BET bromodomain protein, BRD4, is a potential therapeutic target in ovarian carcinoma

“…Among the novel candidate therapeutic target genes identified, BRD4 has been recently reported to be a gene of interest in several hematological malignancies and solid tumors (20)(21)(22)(23)(25)(26)(27)(28)(29)(30). Sensitivity to its inhibition in other cancer cell species correlated with high levels of expression of either MYCN or c-MYC (21-23, 25, 26, 28).…”

The BET Bromodomain Inhibitor I-BET151 Acts Downstream of Smoothened Protein to Abrogate the Growth of Hedgehog Protein-driven Cancers

“…Inhibiting Brd2 or Brd4 in medulloblastoma with brain-penetrant versions of BET inhibitors may be therapeutically attractive. JQ1 is a well characterized, brain-penetrant BET bromodomain inhibitor (12) that has shown efficacy in preclinical models of brain cancer (9,37). However, JQ1 suffers from chemical liabilities that make it unsuitable for clinical testing (28).…”