Selective HDAC1/HDAC2 Inhibitors Induce Neuroblastoma Differentiation

Abstract

Summary While cytotoxic chemotherapy remains the hallmark of cancer treatment, intensive regimens fall short in many malignancies, including high-risk neuroblastoma. One alternative strategy is to therapeutically promote tumor differentiation. We created a gene expression signature to measure neuroblast maturation, adapted it to a high-throughput platform, and screened a diversity oriented synthesis-generated small-molecule library for differentiation inducers. We identified BRD8430, containing a nine-membered lactam, an ortho-amino anilide functionality, and three chiral centers, as a selective Class I histone deacetylase (HDAC) inhibitor (HDAC1>2>3). Further investigation demonstrated that selective HDAC1/HDAC2 inhibition using compounds or RNA interference induced differentiation and decreased viability in neuroblastoma cell lines. Combined treatment with 13-cis retinoic acid augmented these effects and enhanced activation of retinoic acid signaling. Therefore, by applying a chemical genomic screening approach we identified selective HDAC1/HDAC2 inhibition as a strategy to induce neuroblastoma differentiation.

CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2

“…The synergy of GSK126 and panobinostat is strong across a broad concentration range in all 4 of the MYCN-amplified neuroblastoma cell lines tested ( Figure 10B and Supplemental Figure 6). Our laboratory has previously demonstrated that HDAC1/2 inhibition induces neuroblastoma differentiation (55). Moreover, HDAC2 scored as one of the top neuroblastoma-specific dependency genes in the genome-scale CRISPR-Cas9 screen.…”

Therapeutic Strategies to Inhibit MYC

“…PIM-1 inhibitors are in development as antitumor agents, including the ADP-competitive inhibitor SGI-1776. Additional small molecules targeting MYCassociated transcriptional regulators such as HDAC1, HDAC2 (Peart et al 2005;Frumm et al 2013), TFIIH (Titov et al 2011), P53-MDM2 (Felsher et al 2000), and DOT1L (Daigle et al 2011) are referenced in Table 1.…”

Bromodomain and extraterminal inhibition blocks tumor progression and promotes differentiation in neuroblastoma

“…HDAC inhibition was recently demonstrated to enhance neuroblastoma differentiation. 25 Our investigation provides further evidence to highlight the therapeutic potential of targeting epigenetic regulators to promote neuroblastoma differentiation. Overall, preclinical trials, including our own, have demonstrated the pleotropic effects of JQ1 on neuroblastoma apoptosis, growth arrest, and differentiation and provide guidance for therapeutic strategies for the use of BET inhibitors in the treatment of high-risk neuroblastoma.…”