Jingzhuda (entinostat)

P2, N=143, Completed, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | N=101 --> 143

P1/2, N=107, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Dec 2025

6c (chlopynostat) was identified as a potent HDAC1i with a superior profile over entinostat...To sum up, HDAC1 inhibition is necessary to reactivate STAT4/p66Shc expression in patients with CLL. 6c is one of the most potent HDAC1is known to date and represents a novel pharmacological tool for reversing the impairment of the STAT4/p66Shc apoptotic machinery.

P2, N=58, Active, not recruiting, National Cancer Institute (NCI)

P1, N=28, Active, not recruiting, National Cancer Institute (NCI) | Phase classification: P1b --> P1 | Trial completion date: Jun 2023 --> Mar 2025

A quantitative proteomic analysis of MCs treated with MS-275, an HDAC1-3 inhibitor, unveiled altered expression of several proteins, including inflammatory cytokines/chemokines and interferon-stimulated genes (ISGs)...Collectively, our findings underline the significance of viral infections in acquiring a mesenchymal-like phenotype by MCs and the potential consequences of virus-associated peritonitis episodes for PD patients. The observed promotion of MMT reversal and interferon response inhibition by an HDAC1-3 inhibitor, albeit without a general impact on inflammatory cytokine production, has translational implications deserving further analysis.

P1/2, N=91, Recruiting, University Hospital Heidelberg | Trial completion date: Jun 2025 --> Jun 2027 | Trial primary completion date: Jun 2024 --> Jun 2026

There remains a need for postoperative adjuvant drug therapy for the subpopulation of breast cancer patients with high-risk residual cancer after curative therapy. This trial is registered with NCT03473639.

Exploratory analyses revealed that changes in myeloid cells may contribute to responses; however, no correlation was noted between changes in CD8:FoxP3 ratio, PD-L1 status and tumor mutational burden and response. These findings support further investigation of this treatment in a phase II trial.

In this work, we designed PCPA-entinostat conjugates for selective cancer cell targeting. PCPA-entinostat conjugate 12 with a 4-oxybenzyl group linker released entinostat in the presence of LSD1 in in vitro assays and selectively inhibited the growth of cancer cells in preference to normal cells, suggesting the potential of PCPA-entinostat conjugates as novel anticancer drug delivery small molecules.

Our study unveils a direct impact of HDAC-1/2 in the regulation of MC/EOC adhesion and highlights the regulation of MC plasticity by epigenetic inhibition as a potential target for therapeutic intervention in EOC peritoneal metastasis.

P2, N=47, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting

P1/2, N=140, Completed, Syndax Pharmaceuticals | Phase classification: P1b/2 --> P1/2

ONC201, ONC206, and ONC212 are imipridones showing pro-apoptotic anti-cancer response...Additionally, pediatric solid tumor cells were treated with single-agent therapy with histone deacetylase inhibitors (HDACi) vorinostat, entinostat, and panobinostat, showing cell killing with all 3 HDACi drugs, with panobinostat showing the greatest potency...Our results introduce a novel class of small molecules to treat pediatric solid tumors in a precision medicine framework. Use of impridones in pediatric oncology is novel and shows promising pre-clinical efficacy in pediatric solid tumors, including in combination with HDAC inhibitors.

Our study identifies the combination of class I HDACi and BCL-XL inhibitors as a potential new approach for the treatment of MYC-amplified MB cells. Graphical abstract created with BioRender.com, illustrating the workflow and summarizing main results.

We focused our analysis on the most potent ACE2/TMPRSS2 inducer among the inhibitors analysed, MS-275, a HDAC1-3 inhibitor...This study highlights a previously unrecognized effect of HDAC1-3 inhibition in increasing SARS-CoV-2 cell entry, replication and productive infection correlating with increased expression of ACE2 and TMPRSS2. These data, while adding basic insight into COVID-19 pathogenesis, warn for the use of HDAC inhibitors in SARS-CoV-2 patients.

P1/2, N=50, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

HDAC depletion in cancer-associated fibroblasts (CAFs) and treatment with the HDAC inhibitor entinostat (Ent) in PDAC mouse models reduce stromal activation and curb tumor progression. Notably, HDAC inhibition (HDACi) enriches a lipogenic fibroblast subpopulation, a potential precursor for myofibroblasts in the PDAC stroma. Overall, our study reveals the stromal targeting potential of HDACi, highlighting the utility of this epigenetic modulating approach in PDAC therapeutics.

P2, N=20, Active, not recruiting, UNC Lineberger Comprehensive Cancer Center | Recruiting --> Active, not recruiting | Trial completion date: Jun 2024 --> Oct 2026

P2, N=29, Completed, Vastra Gotaland Region | Active, not recruiting --> Completed | Trial completion date: Aug 2023 --> Jan 2023 | Trial primary completion date: Aug 2021 --> Jan 2023

To conclude, tumoral uptake levels of radiolabeled DOTA-TATE were not enhanced after HDACi treatment in vivo, but, depending on the applied inhibitor, increased SSTR2 expression levels were observed.

The doxycycline-induced Kras activation resulted in decreased S100PBP levels, while low-dose treatment with HDAC inhibitor MS-275 rescued its expression in both human and mouse PDAC cell lines. This indicates Kras as an upstream epigenetic regulator of S100PBP. Finally, analysis of TCGA PanCancer Atlas PDAC datasets demonstrated poor prognosis in patients with high S100P and low S100PBP expression, suggesting that S100PBP is a novel tumour suppressor gene with potential clinical utility.

Our study identifies the combination of entinostat with olaparib as a new potential therapeutic approach for MYC-driven Group 3 MB.

Entinostat was identified as a potential small molecule compound to reverse high RCB after NAC...This study established a molecular classification scheme associated with tumor metabolism and cancer cell senescence to predict RCB and DRFS in BC patients after NAC. Furthermore, GATA3 was identified and validated as a key gene associated with BC recurrence.

SALL4 may be a new therapeutic target for the treatment of gastric cancer, and entinostat is a potential novel agent for the treatment of gastric cancer partially by targeting SALL4.

P2, N=20, Recruiting, UNC Lineberger Comprehensive Cancer Center | Trial completion date: Nov 2023 --> Jun 2024 | Trial primary completion date: Oct 2023 --> Mar 2024

Using Cmap analysis, we identify Entinostat and AACOCF3 as potential inhibitors of NUSAP1-mediated pro-oncogenic effects. In vitro and in vivo experiments further confirm that NUSAP1 knockdown significantly reduces the proliferation ability of A549 and MCF-7 cells. Overall, our study highlights the potential of NUSAP1 expression as a novel biomarker for predicting prognosis and immuno-therapeutic efficacy across different human cancers and suggests its potential for developing novel antitumor drugs or improving immunotherapy.

P1, N=3, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Feb 2024 --> Jul 2023

To achieve multifaceted regulation on antitumor immunity against triple-negative breast cancer, in this work, a micelle, termed BEM, co-delivering the MDSC inhibitor, entinostat (ENT), and the immune checkpoint inhibitor, BMS-1, was constructed with pH-sensitive amphiphilic poly(β-amino ester) derivatives...The activated innate and adaptive antitumor immune responses suppressed the growth and metastasis of tumors and prolonged survival of 4T1 tumor-bearing mice. BEN provides a reliable approach for improving cancer immunotherapy by destroying the immunosuppression web in tumors via multinode regulation.

Importantly, in a mouse model, the combination of cisplatin and entinostat also resulted in stronger growth inhibition than each treatment alone. Our study highlights YB-1 as an attractive target in PM and demonstrates that targeting YB-1 via entinostat is a promising approach to enhance cisplatin and radiation sensitivity.

P1/2, N=138, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=57, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Feb 2024 --> Aug 2024

Both low muscle mass and density are prevalent in patients with hormone receptor-positive metastatic breast cancer. Muscle measures correlated with obesity and performance status; however, neither muscle mass nor attenuation were associated with prognosis. Further work is needed to refine body composition measurements and select optimal cutoffs with meaningful endpoints in specific breast cancer populations, particularly those living with metastatic disease.

Finally, we found that CALB2 and GPX3 were remarkably associated with the drug sensitivity of MG-132, Dasatinib, Shikonin, Midostaurin, MS-275, and Z-LNle-CHO, which were expected to be the drugs of choice for GEM combination. CALB2 and GPX3 represent prognostic biomarkers for CRC and they might be potential action targets for GEM. Our study offered innovative ideas for GEM administration strategies.

P3, N=608, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2028 --> Jun 2024

P1b/2, N=196, Completed, Syndax Pharmaceuticals | Active, not recruiting --> Completed | Trial completion date: Jul 2023 --> Sep 2022

Enoxacin and entinostat were the most effective adjuvant drug in both long-term in vitro and in vivo adjuvant studies. In the context that enoxacin is an FDA-approved antibiotic, and that entinostat is an investigational agent not yet FDA-approved, we propose enoxacin as an adjuvant drug for further preclinical and clinical investigation in EWS patients.

We showed that the histone deacetylase inhibitor (HDACI) MS-275, immune-sensitized OS cells to NK cell-mediated lysis...Additionally, culture media was collected for cytokine analysis. NK cells were also analyzed by flow cytometry to measure differences in CD56, CD16, NK activating receptor NKG2D, Ki67, Granzyme B and IFN

We innovatively developed a histone modification-related prognostic model with high prognostic potency and identified YWHAH as possible diagnostic and therapeutic biomarkers for prostate cancer. It provides novel insights to address prostate cancer and enhance clinical outcomes, thereby opening up a new avenue for customized treatment alternatives.

Tumor burden-induced pathway changes can be reversed through epigenetic reprogramming, enabling the conversion from T-cell exhaustion to effector lineage differentiation.

Addition of entinostat to atezolizumab, carboplatin, and etoposide is unsafe and resulted in early onset and severe neutropenia, thrombocytopenia. Further exploration of entinostat with carboplatin, etoposide, and atezolizumab should not be explored. (ClinicalTrials.gov Identifier: NCT04631029).