Jingzhuda (entinostat) / Syndax Pharma, EOC Pharma, EddingPharm - LARVOL DELTA

HDAC and CDK inhibitor combinations suppress neutrophil activation in myeloma (ASH 2025) - "To overcome translational barriers associated with dinaciclib and entinostat, we evaluated next-generation agents: KB0742, a selective and orally bioavailable CDK9 inhibitor, in combination with quisinostat or zabadinostat , two potent HDAC inhibitors with more favorable pharmacokinetic and safety profiles. These transcriptional changes, accompanied by increased re-expression of tumor suppressors (e.g.,p16) and TGFβ/SMAD signaling components, would predict reprogramming of an anti-inflammatory microenvironment by these combination treatments in myeloma. These findings point to a promising but underdeveloped therapeutic avenue whereby suppressing neutrophil-driven inflammation enhances anti-myeloma immunity."

Hematological Malignancies • Multiple Myeloma • Smoldering Multiple Myeloma • BCL2L1 • CXCL1 • CXCL8 • IL1A • IL23A • ITGAM • NRAS • SDC1

HMGA1 chromatin regulators drive transcriptional networks governing cell cycle progression, immune escape, and menin-inhibitor resistance in KMT2A-r Acute Myeloid Leukemia (ASH 2025) - "Leveraging drug predictionalgorithms, we identified candidate compounds to target HMGA1 networks, which include the histonedeacetylase inhibitor (HDACi) entinostat (ENT), that promotes chromatin opening... HMGA1 is required for salient leukemogenic properties in KMT2A-r AML preclinical models.Mechanistically, HMGA1 activates genes governing cell cycle progression, particularly those implicated inmenin inhibitor resistance, while repressing anti-tumor, immune attack genes. Further, these networkscan be targeted with clinically available drugs. Together, these findings implicate HMGA1 as a novelepigenetic regulator and promising therapeutic target in KMT2A-r AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Solid Tumor • CD14 • HMGA1 • HOXA10 • HOXA9 • ITGAM • KMT2A • MEIS1

Integrated dissociated and spatial single-cell profiling reveals that HDAC inhibition restores anti-PD-1 sensitivity in Hodgkin lymphoma by disrupting monocyte-Hodgkin-reed-sternberg cell-driven immunosuppressive niches. (ASH 2025) - "In the present study, we leveraged single-cell combined indexing of transcriptomeand epitopes (CITE)-sequencing and high-resolution spatial transcriptomics to characterize the circulatingand microenvironmental features associated with response to combined HDACi and PD-1 blockade in R/RHL.MethodsOur group recently completed a phase II trial evaluating entinostat plus pembrolizumab in R/R HL (Stuveret al., ASH 2024). Our integrative single-cell and spatial analysis reveals that adaptive immune networks and localizedimmunosuppressive niches critically shape the response to checkpoint blockade in Hodgkin lymphoma.From these findings, the spatial organization of the tumor microenvironment emerges as a criticaldeterminant of therapeutic sensitivity and a promising target for intervention."

IO biomarker • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • B2M • CCR4 • CD4 • CD74 • CD8 • HLA-B • HLA-DRA • IL1B • NLRP3 • RUNX1 • STAT6

Identification of 2 Ubiquitin-Proteasome System-Related Subtypes in Esophageal Squamous Cell Carcinoma for Prognostic and Immunotherapeutic Response Prediction. (PubMed, J Immunother) - "Selumetinib, entinostat, and erlotinib were identified as candidate drugs for cluster 2, whereas tozasertib, alpelisib, and cediranib showed higher suitability for cluster 1. Ten potential biomarkers, 13 transcription factors, and 2 miRNAs were characterized. This study elucidates the role of UPS in ESCC progression and provides a framework for personalized treatment strategies."

IO biomarker • Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • Targeted Protein Degradation • CD8 • TP53

The impact of histone deacetylase inhibition on neurobehavioural outcomes in preclinical models of traumatic and non-traumatic spinal cord injury: a systematic review. (PubMed, Front Immunol) - "Valproate was the most frequently studied HDAC inhibitor (n=20), followed by 4-phenylbutyrate (4-PBA; n=7) and RGFP966 (n=3). Trichostatin A, tubastatin A, entinostat, PCI-34051, scriptaid, CI-994, TMP269, vorinostat, 3-TYP, SW-100 and ACY1215 were each evaluated in a single study. Three studies used the sirtuin-1 (HDAC class III) inhibitor EX527 administered with an activator molecule: melatonin (n=1), MLN4924 (n=1) and oxymatrine (n=1)...These results support further investigation of HDAC inhibitors in preclinical studies before translation into clinical trials. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023477882."

Journal • Preclinical • Review • CNS Disorders • Orthopedics • Pain • Psychiatry • Reperfusion Injury • SIRT1

Melanoma to rhabdomyosarcoma plasticity in the setting of immunotherapy. (PubMed, medRxiv) - "We present a case of a man in his 70s with metastatic melanoma who experienced progression through sequential treatments including pembrolizumab in combination with the HDAC inhibitor entinostat, and ipilimumab. Transdifferentiation has been observed in a wide range of malignancies, but the molecular mechanisms of this phenomenon are poorly understood. This case provides the first molecularly validated example of melanoma to rhabdomyosarcoma transdifferentiation presenting as spatially segregated metastatic lesions with distinct, unmixed histologies and illustrates a mechanism of resistance to immunotherapy driven by phenotypic plasticity."

IO biomarker • Journal • Melanoma • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • CD163 • NF1 • NRAS

Cancer systems immunology unravels complexity of reversing immune suppression and predicts beyond RECIST in metastatic breast cancer (SABCS 2025) - "The epigenetic modulator, entinostat when combined with dual checkpoint blockade; nivolumab and ipilimumab demonstrated promising results in our Phase Ib trial (NCI-0944) and in our recent meta-analysis (AACR-3225, 2025). We conclude that epigenetic modulation via HDACi induces a carefully orchestrated set of changes in plasma cells and CD8 T cells with MDSCs and macrophages to sensitize the TME to checkpoint inhibition. Significant changes in TLS formation and macrophage -T cell interactions in biopsies from patient responders validate findings. More broadly we provide a framework for the discovery of cell-cell interactions that control responses in complex TMEs."

Metastases • Breast Cancer • Oncology • Solid Tumor • CD8

Entinostat & Chemotherapy for Locally Advanced or Metastatic Bladder Cancer (clinicaltrials.gov) - P1/2 | N=29 | Not yet recruiting | Sponsor: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

New P1/2 trial • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor

Targeting H3K27M protein with inhibitors of histone deacetylases in H3K27-altered diffuse midline gliomas (SNO 2025) - "Importantly, we have recently shown that some HDACi (including panobinostat, pracinostat/SB939, vorinostat and entinostat) lead to the reduction in the H3K27M protein levels. We are hoping that our studies may pave the way for new therapeutic strategies for patients with DMGs, aiming at eradication of detrimental H3K27M oncohistone protein. The study is supported by the Sonata Bis-14 grant (2024/54/E/NZ3/00480) awarded by the National Science Centre, Poland."

Epigenetic controller • Brain Cancer • Diffuse Midline Glioma • Glioma • High Grade Glioma • Solid Tumor

Comparative Study of Histone Deacetylase Inhibitors for Radiation Protection Using Survival Outcomes in a Mouse Model. (PubMed, Biol Pharm Bull) - "Male ICR mice received 7.5 Gy TBI followed by a single administration of valproic acid (VPA; 300 or 600 mg/kg), sodium butyrate (NaB; 500 or 1000 mg/kg), trichostatin A (TSA; 0.5 or 1.0 mg/kg), vorinostat (10 or 50 mg/kg), panobinostat (25 or 50 mg/kg), givinostat (5 or 10 mg/kg), or entinostat (25 or 50 mg/kg). VPA's efficacy may reflect a combination of effects on DNA repair, inflammation, and redox regulation rather than HDAC inhibition alone. These findings suggest VPA to be a promising candidate for radioprotection and emphasize the need for further studies to optimize dosing and explore underlying mechanisms."

Clinical • Journal • Preclinical • Inflammation

Xenograft tissue slice tandem co-cultures are a highly specific model to selectively analyze drug inhibitory effects on glioblastoma invasion. (PubMed, J Biol Chem) - "The established chemotherapeutic Temozolomide (TMZ) and three promising candidates - two histone deacetylase (HDAC) inhibitors, Vorinostat and Entinostat, and the neuropeptide Apamin - were tested. Despite the absence of inhibitory effects of Apamin in 2D cell culture, G55T2 XTCCs revealed ∼70% reduced GBM invasion, associated with a substantial inhibition of proliferation as indicated by loss of Ki-67 positivity. Taken together, we show the suitability of the XTCC models for monitoring tumor growth and, in particular anti-invasive effects of drugs."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Final Response and Survival Results from a Phase II Trial of Pembrolizumab and Entinostat in Relapsed/Refractory Hodgkin Lymphoma (ASH 2024) - "Prior therapies included brentuximab vedotin (82%), anti-PD1 (74%), HDAC inhibitor (10%), and/or autoHCT (67%). Toxicities were primarily hematologic, with two notable pericardial events which led to drug discontinuation. Overall, HDAC inhibition in combination with anti-PD1 blockade is effective in HL, even in patients with prior anti-PD1 exposure and/or resistance."

IO biomarker • P2 data • Cardiovascular • Classical Hodgkin Lymphoma • Hematological Disorders • Hematological Malignancies • Hodgkin Lymphoma • Infectious Disease • Inflammation • Lymphoma • Neutropenia • Novel Coronavirus Disease • Oncology • Pneumonia • Thrombocytopenia

Portfolio analysis of single-cell RNA-sequencing and transcriptomic data unravels immune cells and telomere-related biomarkers in sepsis. (PubMed, Front Immunol) - "Finally, we obtained a candidate drug (MS-275) and a key cell (CD16+ and CD14+ monocytes) respectively based on drug prediction and cell identification analysis...The RT-qPCR results showed biomarkers were upregulated in the sepsis group, consistent with the bioinformatics analysis results. This study identified 4 biomarkers, namely MYO10, SULT1B1, MKI67, and CREB5 and explored the pathogenesis of sepsis, providing new insights for potential treatment strategies by integrating transcriptomic data and single-cell analysis."

Biomarker • Journal • Infectious Disease • Septic Shock • CD14 • CREB5

A Study of Entinostat in Combination With Fulvestrant for the Treatment of Locally Advanced or Metastatic Breast Cancer (clinicaltrials.gov) - P2 | N=50 | Not yet recruiting | Sponsor: Sun Yat-sen University

New P2 trial • Breast Cancer • Oncology • Solid Tumor

Targeting HDAC3 dynamics: Allosteric role of Phe200 in inhibitor binding and breast cancer therapy. (PubMed, J Mol Graph Model) - "Among the compounds, domatinostat and entinostat exhibited the strongest affinities (ΔGbind ≈ -70 kcal/mol), in reasonable agreement with experimental data (r = 0.60). This supports an allosteric inhibition mechanism in which ligands lock HDAC3 into inactive conformations. Collectively, these findings offer mechanistic insights into HDAC3 regulation and highlight structural hot spots for the rational design of selective inhibitors with potential applications in targeted breast cancer therapy."

Journal • Breast Cancer • Oncology • Solid Tumor • HDAC3

Targeting H3K27M protein with inhibitors of histone deacetylases in H3K27-altered diffuse midline gliomas (WFNOS 2025) - "Importantly, we have recently shown that some HDACi (including panobinostat, pracinostat/SB939, vorinostat and entinostat) lead to the reduction in the H3K27M protein levels. We are hoping that our studies may pave the way for new therapeutic strategies for patients with DMGs, aiming at eradication of detrimental H3K27M oncohistone protein. The study is supported by the Sonata Bis-14 grant (2024/54/E/NZ3/00480) awarded by the National Science Centre, Poland."

Epigenetic controller • Brain Cancer • Diffuse Midline Glioma • Solid Tumor

HMGA1 Chromatin Regulators Drive Immune Evasion in MPN Progression through Epigenetic Rewiring to Repress Antigen Presentation (ASH 2023) - "We discovered a novel epigenetic program whereby HMGA1 drives immune evasion during MPN progression by repressing MHC Class II genes. We also define a new mechanism of gene repression by HMGA1 through chromatin compaction and repressive histone marks that preclude CTCF binding to the MHC Class II loci. Both HMGA1 depletion and entinostat up-regulate MHC Class II genes, thus unveiling HMGA1 as a therapeutic target to stimulate an immune attack and prevent MPN progression."

Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Solid Tumor • CD74 • HLA-DPB1 • HLA-DRA • HLA-DRB1 • IFNG

PTBP1, an RNA Binding Protein and Splicing Regulator, Binds RUNX1 and Co-Localizes at Target Gene Promoters in Leukemia (ASH 2024) - "To test whether HDAC1 activity regulates the interaction of RUNX1 with other co-factors, we performed a mass spectrometry screen for RUNX1 binding partners in the presence or absence of the HDAC1 inhibitor, entinostat...We also show that PTBP1 co-localizes with RUNX1 at the promoters of transcriptionally active genes and regulates key metabolic genes. Collectively, our results suggest that PTBP1 cooperates with RUNX1 to promote expression and splicing of key leukemogenic targets."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CD34 • PTBP1 • RUNX1 • SLC2A3

HMGA1 Chromatin Regulators Disrupt 3D Genome Architecture and Chromatin Looping to Repress MHC II Genes and Drive Immune Evasion during MPN Progression (ASH 2024) - "We also define a new mechanism of immune evasion by HMGA1 through chromatin compaction and repressive histone marks that disrupt CTCF-mediated loop formation required to activate MHC II genes. Both HMGA1 depletion or entinostat up-regulate MHC II to activate cytotoxic T cells, thus illuminating HMGA1 as a therapeutic target to stimulate an immune attack and prevent MPN progression."

Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • Solid Tumor • CD34 • CD74 • HLA-DPB1 • HLA-DRA • HLA-DRB1 • HMGA1 • IFNG • TP53

Risk model of liquid-liquid phase separation-related genes reveals the prognosis and tumor microenvironment characteristics of colorectal cancer. (PubMed, J Cell Commun Signal) - "Drug sensitivity analysis suggested therapeutic efficacy of Entinostat and 5-fluorouracil in this subgroup. Our study provides the first LLPS-associated prognostic framework for CRC, offering both a risk stratification tool and actionable therapeutic insights. The findings highlight LLPS as a critical molecular organizer in CRC pathogenesis and a potential target for precision oncology approaches."

Biomarker • Journal • Tumor mutational burden • Colorectal Cancer • Oncology • Solid Tumor • ASXL1 • DDX21 • TACC3 • TMB • TRIM28

A novel TCRβ-directed IL-2 fusion molecule promotes memory CD8+ T cells with self-renewing properties in tumor ecosystems, further expanded by HDAC inhibition to elicit effective tumor suppression (SITC 2025) - "Here, we examined the tumor-suppressive ability and mode of action of a murine surrogate of STAR0602 (mSTAR1302), which targets the prevalent murine TCRVβ13.2/13.3, in combination with the class I HDAC inhibitor (HDACi) Entinostat, an epigenetic modulator that enhances tumor immune recognition, in multiple tumor models irrespective of ICB responsiveness.Methods mSTAR1302 and/or Entinostat were administered to mice bearing ICB-responsive breast (EMT6) and ICB-refractory colorectal (CT26; KRasG12Dmut) tumors. These effects are associated with TCRVβ13/IL-2R targeting augmenting CD8+ T cell self-renewal properties, further enhanced with HDACi combination. Collectively, this data supports the clinical use of STAR0602 in combination with HDAC inhibitors for patients harboring solid malignancies irrespective of ICB sensitivity."

Oncology • Solid Tumor • CD4 • CD8 • IFNG • IL2 • IL2RA • KRAS • TRB

Anti-CD40 and Epigenetic Modifier Inhibitors to Augment Treatment of High-Risk Neuroblastoma (SITC 2025) - "We identified inhibitors of DNMTs (guadecitabine, 'Guad') and HDACs (entinostat, 'Ent') that, when combined with aGD2 and aCD40, cause tumor regression.Methods HR-NBL cells were treated with EMis and assessed for MHCI expression changes via qPCR and flow cytometry. Therapies geared towards restoring MHCI expression, combined with effective immunotherapy regimens that allow for persistent immune responses, might augment immune responses and improve efficacy of combination immunotherapy for HR-NBL.Ethics Approval Our research is conducted under strict oversight by the IACUC and in compliance with all applicable federal and institutional policies.Acknowledgements This research was supported by Midwest Athletes Against Childhood Cancer; and by public health service grants from the National Cancer Institute: Alex's Lemonade Stand Foundation, the Hartwell Foundation, Midwest Athletes Against Childhood Cancer, R35 CA197078, U54 CA232568 as well as the Data..."

IO biomarker • Neuroblastoma • Oncology • Solid Tumor

Intratumoral IL-12 in combination with HDAC inhibition overcomes checkpoint-refractory tumors (SITC 2025) - "In this study, we investigated the anti-tumor activity and mechanism of action of murine ANK-101 (mANK-101) delivered intratumorally in combination with the class I histone deacetylase (HDAC) inhibitor entinostat, in different ICB-refractory murine tumor models, including CT26 (colorectal) and MOC-1 (HPV16neg head and neck).Methods Mice receiving Entinostat diet and/or mANK-101 were monitored for anti-tumor activity, survival and protective memory. Notably, spatial analysis of tumor architecture indicates the development of B-cell rich stemness hubs exclusive to combination therapy. Ongoing in-depth studies including single cell transcriptomics in the tumor and tDLN, and investigation of the role of immune stemness hubs in the observed anti-tumor activity will allow for an in-depth understanding of the synergistic effect of mANK-101 with HDAC inhibition.Conclusions Collectively, these findings provide a rationale for the combination of intratumoral delivery of anchored..."

Combination therapy • Head and Neck Cancer • Oncology • Solid Tumor • CD4 • CD8 • IFNG • IL12A • KRAS • TNFA

Epigenetic modulation synergizes with TCRβ-targeted IL-2 to yield CD8+ T cell dependent, MHC-I independent tumor control via an antibody associated mechanism (SITC 2025) - "Here, we examined the tumor-suppressive ability and mode of action of a murine surrogate of STAR0602 (mSTAR1302), which targets murine TCRVβ13.2/13.3, in combination with the class I HDAC inhibitor (HDACi) Entinostat, an epigenetic modulator that enhances tumor immune cell recognition, in multiple ICB-refractory tumor models devoid of MHC-I.Methods mSTAR1302 and/or Entinostat were administered to mice bearing β2-microglobulin (B2m)-deleted (MHC-Inull) breast (EMT6) and colorectal (MC38) tumors. Ongoing mechanistic investigation of this myeloid/lymphoid crosstalk in MHC-I+ and MHC-Inull tumors will provide deeper insight into the mode of action of this combination therapy.Conclusions Collectively, these data highlight an alternative mechanism of tumor suppression when direct MHC-I/TCR engagement is absent. This supports the use of STAR0602 in combination with HDAC inhibitors for the treatment of solid malignancies including those resistant to current ICB therapies."

Colorectal Cancer • Oncology • Solid Tumor • B2M • CD4 • CD8 • IL2 • IL2RA • TRB

T cell interactions and B cell activation mediate response to treatment with entinostat and checkpoint inhibitors in metastatic breast cancer (SITC 2025) - "The Sidney Kimmel Comprehensive Cancer Center Clinical Research Review Committee and Safety Monitoring Committee were responsible for reviewing accrual and safety data for this trial at least twice a year. The Protocol Chair and the study statistician reviewed the study as needed based on rate of accrual for toxicity monitoring during the dose expansion phase at least quarterly."

Checkpoint inhibition • IO biomarker • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8 • HER-2 • ICAM1 • IFNAR2 • IFNG • IFNGR1 • ITGB2 • TNFRSF9