quisinostat (JNJ 26481585)

Several specific interventions (i.e., Quisinostat, Carnosic acid, hyperbaric oxygen, melatonin, aqueous-soluble sporoderm-removed G. lucidum spore powder, and disulfiram/copper complex) were found to dramatically induce ferroptosis cell death of OSCC via multiple mechanisms. This review highlighted the pivotal role of ferroptosis in the pathogenesis and prognosis of OSCC. Future anticancer therapeutic strategies targeting ferroptosis and its associated molecules might provide a new insight for OSCC treatment.

In current studies, targeting ΔNp63 with inducible CRISPR knockout and Histone deacetylase inhibitor Quisinostat showed that ΔNp63 is important for tumor progression and metastasis in established tumors by promoting myeloid-derived suppressor cell (MDSC) survival through tumor necrosis factor alpha...We further demonstrated that targeting ΔNp63 sensitizes chemotherapy. Overall, we showed that ΔNp63 reprograms the MDSC-mediated immunosuppressive functions in TNBC, highlighting the benefit of targeting ΔNp63 in chemotherapy-resistant TNBC.

Furthermore, to investigate the detailed mechanisms in the antitumor effects of HDAC inhibitors for NSCLC via CGN and FOXO1, A549 cells and HLE cells were treated with the HDAC inhibitors trichostatin A (TSA) and Quisinostat (JNJ-2648158). In conclusion, the knockdown of CGN via FOXO1 contributes to the malignancy of NSCLC. Both HDAC inhibitors, TSA and Quisinostat, may have potential for use in therapy for lung adenocarcinoma via changes in the expression of CGN and FOXO1.

The pharmacokinetic-pharmacodynamic-efficacy relationship was established by correlating free drug concentrations and evidence of target modulation in the brain with survival benefit. Together, these data provide a strong rationale for clinical development of quisinostat as a radiosensitizer for the treatment of GBM.

We screened PBT-24FH cells for sensitivity to a panel of HDAC inhibitors (HDACis) in vitro, identifying two HDACis associated with low nanomolar IC50s, quisinostat (27 nM) and romidepsin (2 nM). Here, we establish the preclinical efficacy of quisinostat against hypermutant DIPG, supporting further investigation of epigenetic targeting of hypermutant pediatric cancers with the potential for clinical translation. These findings support further investigation of HDAC inhibitors against pontine high-grade gliomas, beyond only those with histone mutations, as well as against other hypermutant central nervous system tumors.

Additionally, quisinostat can also sensitize BC cells to erdafitinib by downregulating HDGF. This study discovers a new avenue for treatment of FGFR3-driven BC and uncovers new mechanistic insights. These preclinical studies pave the way for a direct translation of this combination to early phase clinical trials.

Metastasis formation could be reduced by navitoclax and more efficiently by the combinations navitoclax/everolimus and flavopiridol/quisinostat. Importantly, the ferroptosis-related genes GPX4 and SLC7A11 are negatively correlated with the survival of UM patients (TCGA: n = 80; Leiden University Medical Centre cohort: n = 64), ferroptosis susceptibility is correlated with loss of BAP1, one of the key prognosticators for metastatic UM, and ferroptosis induction greatly reduced metastasis formation in the UM xenograft model. Collectively, we have established a patient-derived animal model for metastatic UM and identified ferroptosis induction as a possible therapeutic strategy for the treatment of UM patients.

Combining quisinostat with either cisplatin or the PARP inhibitor (PARPi) talazoparib improved its efficiency in UC cell lines. Synergy mechanisms involve caspase-dependent apoptosis and cell cycle disruption. RNA-Seq analysis and in vivo experiments are ongoing to better characterise these interesting therapy options.

The markedly different sensitivity of these models enables mechanistic study of the consequences of elevated abundance of histone 3 acetylation. The long term goal is to discover a molecular profile of DMGs indicative of the vulnerability to HDACi.

The second generation histone deacetylase inhibitor (HDACi) quisinostat, which targets HDAC1; was shown to have moderate effects on cell cycle distribution and apoptosis induction in urothelial carcinoma cell lines (UCC) and to be tolerated by the normal uroepithelial HBLAK at higher doses compared to other HDACi such as romidepsin. Conclusion Quisinostat is suitable for a combination with cisplatin and talazoparib at reduced dosage with low normal cell toxicity. Further analyses including RNA-Seq analysis and mice xenografts are ongoing to understand the underlying mechanisms of these promising combinations.

p63 is not only a diagnostic marker of salivary gland neoplasia, but it also promotes the malignancy. Inhibition of HDAC and signal transduction pathways is, therefore, useful in therapy for p63-positive SDC cells.

Additionally, PDO#207 were sensitive to mTOR (Everolimus), HDAC (Quisinostat), and ATP-competitive protein kinase (Saurosporine) inhibitors. This study may provide a preclinical tool to screen drug responses to standard of care and newly identified drugs for TNBC.

We found that quisinostat reduces tumor burden in flank and orthotopic models of GBM and extends survival when administered in combination with radiation therapy in vivo. Together, these results provide a rationale for developing quisinostat as a potential combination therapy with radiation in the treatment of GBM.

In vitro evaluation of cell viability revealed the low nanomolar IC 50 of quisinostat (50nM) and romidepsin (2nM). Transcriptomic and proteomic investigations are underway to identify the mechanism of action underlying quisinostat-induced cytotoxicity. Ultimately, we are the first to demonstrate in vivo efficacy of the HDACi quisinostat against hypermutant DIPG, supporting further investigation and clinical advancement.

Pharmacodynamic changes were observed in flank but not in intracranial tumors. CONCLUSION Our data indicate low free quisinostat levels in the brain primarily due to drug instability.

By employing an isogenic cell model, our study showed that BAP1 loss can reprogram miRNA expression in mesothelioma. BAP1 deficiency alone resulted in the silencing of a tumour-suppressive miRNA cluster mapping to chromosome 14q32.31 and whose clinical relevance was confirmed in a subset of BAP1- altered epithelioid MPM cell lines. Preliminary experiments suggest that BAP1 loss co-ordinates with histone deacetylation to repress expression of this miRNA cluster in MPM.

Furthermore, we also observed that autophagy plays an important role in JNJ induced cell differentiation of SK-N-SH cells. We demonstrated that autophagy is induced upon JNJ treatment and is important for the neuronal differentiation of human SK-N-SH cells.

Both HDAC inhibitors prevented disruption of the epithelial barrier measured as the permeability of FD-4 induced by TGF-β in 2.5D culture. TSA and Quisinostat have potential for use in therapy for lung adenocarcinoma via changes in the expression of angulin-1/LSR and CLDN-2.

Up-regulation of the expression of p53 and down-regulated expression of GPX4 in cell lines were observed by immunofluorescent staining, and the expression locations of p53 and GPX4 proteins in TSCC cells were observed. Based on these findings, quisinostat may be a potential drug for the treatment of tongue squamous cell carcinoma.

While in vitro tests showed that Tazemetostat did not influence cell growth, Quisinostat decreased cell survival. Combination therapy mostly followed the Quisinostat results. Our findings indicate that epigenetic drugs (in this case an HDAC inhibitor) may influence the expression of immunologically relevant cell surface molecules in UM, demonstrating that these drugs potentially influence immunotherapy.

Herein, in the current study, we explored the unexplored response of NB cells to the second-generation histone deacetylase inhibitor (HDACi) JNJ-26481585(JNJ) and the lysosomotropic agent, Chloroquine (CQ) alone and upon JNJ/CQ treatment as a plausible therapeutic. Corroborating the above observations, we found that the ROS scavenger N-acetylcysteine (NAC) countered caspase-3 activity and the cells were rescued from apoptosis. Finally, these observations establish that JNJ/CQ treatment resulted in cell death in NB cells by triggering the formation of ROS and disruption of MMP, suggesting that modulation of JNJ-induced autophagy by CQ represents a promising new therapeutic approach in NB.

Using a novel 2-step screening approach, strategy, we identified quisinostat as a candidate for therapy in BAP1-mutant uveal melanoma. HDAC4 is implicated as a key target in uveal melanoma and perhaps other BAP1-mutant cancers.

In several resistant clone cells, pretreatment with the histone deacetylase inhibitor quisinostat helped overcome the resistance by reverting EMT. Furthermore, drug screening from a library of 100 kinase inhibitors indicated that GSK-3 inhibitors, such as LY2090314, markedly inhibited the growth and induced apoptosis of resistant cells, specifically those with a mesenchymal phenotype. These results suggest that GSK-3 inhibition may be useful to circumvent EMT-associated resistance to osimertinib in EGFR mutant lung cancer.