A large-scale drug screen identifies selective inhibitors of class I HDACs as a potential therapeutic option for SHH medulloblastoma

Abstract

Background Medulloblastoma (MB) is one of the most frequent malignant brain tumors of children, and a large set of these tumors is characterized by aberrant activation of the sonic hedgehog (SHH) pathway. While some tumors initially respond to inhibition of the SHH pathway component Smoothened (SMO), tumors ultimately recur due to downstream resistance mechanisms, indicating a need for novel therapeutic options. Methods Here we performed a targeted small-molecule screen on a stable, SHH-dependent murine MB cell line (SMB21). Comprehensive isotype profiling of histone deacetylase (HDAC) inhibitors was performed, and effects of HDAC inhibition were evaluated in cell lines both sensitive and resistant to SMO inhibition. Lastly, distinct mouse models of SHH MB were used to demonstrate pharmacologic efficacy in vivo. Results A subset of the HDAC inhibitors tested significantly inhibit tumor growth of SMB21 cells by preventing SHH pathway activation. Isotype profiling of HDAC inhibitors, together with genetic approaches suggested that concerted inhibition of multiple class I HDACs is necessary to achieve pathway inhibition. Of note, class I HDAC inhibitors were also efficacious in suppressing growth of diverse SMO inhibitor‒resistant clones of SMB21 cells. Finally, we show that the novel HDAC inhibitor quisinostat targets multiple class I HDACs, is well tolerated in mouse models, and robustly inhibits growth of SHH MB cells in vivo as well as in vitro. Conclusions Our data provide strong evidence that quisinostat or other class I HDAC inhibitors might be therapeutically useful for patients with SHH MB, including those resistant to SMO inhibition.

CD13 promotes hepatocellular carcinogenesis and sorafenib resistance by activating HDAC5‐LSD1‐NF‐κB oncogenic signaling

“…Based on the mechanism, we hypothesize the synergistic beneficial effects of ubenimex and the pan HDAC inhibitor Quisinostat, which was reported to inhibit cancer cells self-renewal and the growth of medulloblastoma. 33,34 Tumor cells and xenografts exposed to the combination therapy show inhibited cellular proliferation characterized by lower levels of Cyclin A and D1. It is important to note that the combination therapy is also synergistic in the HCC metastatic PDX models, indicating that the novel combination treatment is not only effective in primary tumor but also metastatic foci.…”

Histone Deacetylase Inhibitors in Pediatric Brain Cancers: Biological Activities and Therapeutic Potential

“…HDACis show more pronounced effects on proliferation of SHH-driven MB cells harboring a mutation in the gene encoding for the histone acetyltransferase (HAT) CREBBP, when compared to CREBBP wild-type controls (Hellwig et al, 2019). A targeted small-molecule screen on the stable, SHH-dependent murine MB cell line SMB21 reveals selective inhibitors of class I HDACs as promising antitumor agents for SHH MB, and the novel class I HDAC inhibitor JNJ-26481585 (quisinostat) consistently inhibits growth of SHH MB in vivo as well as in vitro (Pak et al, 2019). Another recent study using a high-throughput cell viability assay to screen 12,800 compounds identified two HDACis, JNJ-26481585 and dacinostat, as anti-proliferative agents in MB.…”

Leveraging multi-way interactions for systematic prediction of pre-clinical drug combination effects

“…SMO-inhibitor vismodegib blocks Hedgehog pathway which regulates the skin growth. In case of medulloblastoma, HDAC inhibitors are active against even SMO-inhibitor resistant cell lines 37 . Hence, concurrent use of HDAC- and SMO- inhibitors holds a promising strategy to target melanoma, as predicted by romidepsin and vismodegib combination (Fig.…”