AACR 2017 | Poster 4672/3 – Novel epigenetic approach to relapsed Mantle Cell Lymphoma based on dual inhibition of EZH1/EZH2

At the American Association for Cancer Research (AACR) annual meeting in Washington, DC, USA, on Tuesday 4^th April, a poster session titled “Epigenetics and DNA Repair” took place.

One of the posters on display (4672 / 3) was titled “Novel epigenetic approach to relapsed mantle cell lymphoma based on dual inhibition of EZH1/EZH2” by Shuhei Fujita from the National Cancer Center Research Institute, Tokyo, Japan, and colleagues.

The group used OR-S1, a novel dual inhibitor of EZH1/2, to demonstrate that EZH1/2 inhibition is an encouraging therapeutic strategy for MCL. In addition to in vitro assays using MCL cell lines, they orally administered OR-S1 to a xenograft (PDX) murine model, using cells from a heavily pretreated and relapsed MCL patient.

Key Highlights:

• In vitro assays using MCL cell lines demonstrated that OR-S1 inhibited cell growth; the effect was much greater than administration of the single EZH2 inhibitor (GSK126)
• IC₅₀ of OR-S1 was about one tenth of GSK126
• In further analyses of MCL cell lines, those exposed to OR-S1 underwent cell cycle arrest (at G1)
• A dose-dependent reduction in phosphorylated Retinoblastoma protein and cell differentiation was observed
• Administration of OR-S1 increased cell surface expression of hCD138
• RNA-seq analysis of MCL cell lines indicated that cell cycle-related signaling was significantly affected and that CDKN1C (TP57) was one of the genes most markedly upregulated by OR-S1
• ChIP qPCR of MCL cell lines demonstrated that the CDKN1C locus was strongly marked by H3K27 tri-methylation; OR-S1 induced a significant reduction in the level of this histone marker
• OR-S1 strongly inhibited proliferation of patient-derived tumors; no serious side effects reported
• Administration of OR-S1 alone to PDX mice induced increased expression of CDKN1C

In summary, dual inhibition of EZH1/2 increases CDKN1C expression, resulting in cell cycle arrest and inhibition of cell growth in MCL. The poster was concluded by stating that the data presented indicates that dual inhibition of EZH1/2 is a potential therapeutic strategy for patients with MCL.