CUDC907, a dual phosphoinositide-3 kinase/histone deacetylase inhibitor, promotes apoptosis of NF2 Schwannoma cells

Abstract

Neurofibromatosis Type 2 (NF2) is a rare tumor disorder caused by pathogenic variants of the merlin tumor suppressor encoded by NF2 . Patients develop vestibular schwannomas (VS), peripheral schwannomas, meningiomas, and ependymomas. There are no approved drug therapies for NF2. Previous work identified phosphoinositide-3 kinase (PI3K) as a druggable target. Here we screened PI3K pathway inhibitors for efficacy in reducing viability of human schwannoma cells. The lead compound, CUDC907, a dual histone deacetylase (HDAC)/PI3K inhibitor, was further evaluated for its effects on isolated and nerve-grafted schwannoma model cells, and primary VS cells. CUDC907 (3 nM IG 50 ) reduced human merlin deficient Schwann cell (MD-SC) viability and was 5–100 fold selective for MD over WT-SCs. CUDC907 (10 nM) promoted cell cycle arrest and caspase-3/7 activation within 24 h in human MD-SCs. Western blots confirmed a dose-dependent increase in acetylated lysine and decreases in pAKT and YAP. CUDC907 decreased tumor growth rate by 44% in a 14-day treatment regimen, modulated phospho-target levels, and decreased YAP levels. In five primary VS, CUDC907 decreased viability, induced caspase-3/7 cleavage, and reduced YAP levels. Its efficacy correlated with basal phospho-HDAC2 levels. CUDC907 has cytotoxic activity in NF2 schwannoma models and primary VS cells and is a candidate for clinical trials.

Simultaneous inhibition of PI3K and PAK in preclinical models of neurofibromatosis type 2-related schwannomatosis

“…Since we observed a higher cleaved caspase-3 (CC-3) signal after pictilisib treatment in the mouse model, we decided to compare human (HS02) and mouse (MS01) MD-SCs cells in vitro using a previously described Incucyte CC-3/7 assay [ 14 ]. Human MD-SC lines exhibited significantly reduced confluency after pictilisib treatment (Fig.…”

“…Preliminary screening of 193 compounds alone and in combination has been conducted on our mouse and human merlin-deficient Schwann cells by the SYNODOS Consortium. Multiple PI3K inhibitors met criteria for efficacy and/or synergy [ 13 , 14 ]. Although targeted single agent chemotherapeutics can inhibit tumor growth, drug resistance is common due to activation of alternative signaling pathways that sustain cell survival and proliferation [ 15 , 16 ].…”

Activator Protein-1 (AP-1) Signaling Inhibits the Growth of Ewing Sarcoma Cells in Response to DNA Replication Stress

“…We previously identified, in unpublished work, that HDAC inhibitors decrease the level of the RRM1 protein in Ewing sarcoma and other cell types. Figure 5A and B demonstrate that the treatment of Ewing sarcoma cell lines with the pan-HDAC inhibitor fimepinostat reduced the level of the RRM1 protein and inhibited the growth of Ewing sarcoma cell lines in a dose–response growth assay ( 53 ). Fimepinostat is a dual inhibitor of HDAC and PI3K so we then tested two additional HDAC inhibitors that are currently used in the clinic, romidepsin and panobinostat ( 54 ).…”

Quatramer™ encapsulation of dual‐targeted PI3‐Kδ/HDAC6 inhibitor, HSB‐510, suppresses growth of breast cancer

“…administration, resulting in faster excretion and lower tumor accumulation. [34][35][36] Nanoparticle (NP) delivery systems based on biodegradable polymers offer several advantages over free drug molecules. It allows improved pharmacokinetics (PK) of the encapsulated drug molecule with longer blood circulation time, higher accumulation in the tumor with leaky blood vasculature, and poor lymphatic drainage by the enhanced permeability and retention (EPR) effect.…”

“…Moreover, the poor water solubility of dual inhibitor anticancer agents limited their intravenous (i.v.) administration, resulting in faster excretion and lower tumor accumulation 34–36 …”