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

Exemestane With or Without Entinostat in Treating Patients With Recurrent Hormone Receptor-Positive Breast Cancer That is Locally Advanced or Metastatic (clinicaltrials.gov) - P3 | N=608 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2025 ➔ Jun 2026

Trial completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PGR

Pathologic response and safety of neoadjuvant pembrolizumab with or without entinostat in muscle-invasive urothelial cancer (MIUC). (ASCO 2025) - P2 | "Neoadjuvant pembrolizumab with or without entinostat is active in MIUC with an acceptable safety profile. Analysis of the primary endpoint and other translational endpoints is ongoing."

Clinical • IO biomarker • Back Pain • Fatigue • Genito-urinary Cancer • Heart Failure • Musculoskeletal Pain • Oncology • Pain • Solid Tumor • Urothelial Cancer • HDAC1

Dual Targeting EZH2 and Histone Deacetylases in Human Uterine Sarcoma Cells Under Both 2D and 3D Culture Conditions. (PubMed, J Cell Mol Med) - "Our studies demonstrate that treatment with either entinostat or tazemetostat alone showed a potent anti-uterine sarcoma effect in 2D and 3D culture conditions. Importantly, the combination of entinostat and tazemetostat produced superior therapeutic effects, suggesting that dual targeting EZH2 and HDACs may provide a promising treatment option for this aggressive cancer."

Journal • Oncology • Sarcoma • Solid Tumor • HDAC1 • HDAC3

HDAC inhibitors engage MITF and the disease-associated microglia signature to enhance amyloid β uptake. (PubMed, Brain Behav Immun) - "Here, we present a pharmacological approach to mimic human DAM in vitro: we validated in silico predictions that two different histone deacetylase (HDAC) inhibitors, Entinostat and Vorinostat, recapitulate aspects of the DAM signature in two human microglia-like model systems. Further, we functionally characterized our DAM-like model system, showing that the upregulation of this transcriptional program by HDAC inhibitors leads to an upregulation of amyloid β and pHrodo Dextran uptake - while E.coli uptake is reduced - and a specific reduction of MCP1 secretion in response to IFN-γ and TNF-α. Overall, our strategy for compound-driven microglial polarization offers potential for exploring the function of human DAM and for an immunomodulatory strategy around HDAC inhibition."

Journal • CNS Disorders • IFNG • MITF • TNFA

Efficacy and safety of entinostat plus exemestane in hormone receptor-positive breast cancer: a systematic review meta-analysis of randomized controlled trials. (PubMed, Breast Cancer Res Treat) - "The ENT + EXE combination demonstrates significant PFS benefits in HR + breast cancer patients compared to PL + EXE. However, no improvements were seen in OS, ORR, or CBR. In addition, the higher incidence of AEs, especially hematologic and gastrointestinal, highlights the need for careful patient selection and monitoring."

Journal • Retrospective data • Review • Breast Cancer • Hematological Disorders • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Integrative analysis of epigenetic subtypes in acute myeloid Leukemia: A multi-center study combining machine learning for prognostic and therapeutic insights. (PubMed, PLoS One) - "This integrated classification system combining epigenetic features and stem cell signatures provides new insights into AML heterogeneity and therapeutic targeting. The complementary nature of epigenetic and stem cell-related prognostic factors suggests potential for improved risk stratification in clinical practice. Future prospective validation studies are warranted to confirm these findings."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CHRDL1

Predicting gene expression changes upon epigenomic drug treatment. (PubMed, F1000Res) - "Accordingly, several drugs targeting the epigenome have been proposed for cancer therapy, notably, histone deacetylase inhibitors (HDACi) such as vorinostat and DNA methyltransferase inhibitors (DNMTi) such as zebularine...We found that in two cell lines (HCT116 treated with Largazole at eight doses and RH4 treated with Entinostat at 1µM) where the appropriate data (pre-treatment transcriptome and epigenome as well as post-treatment transcriptome) is available, our model distinguished the post-treatment up versus downregulated genes with high accuracy (up to ROC of 0.89)...Here we present a first assessment of the predictability of genome-wide transcriptomic changes upon treatment with HDACi. Lack of appropriate omics data from clinical trials of epigenetic drugs currently hampers the assessment of applicability of our approach in clinical setting."

Journal • Oncology

Little to show for much effort and investment: An industry perspective on MDS drug development (MDS 2025) - "Randomized studies incorporated lenalidomide, vorinostat, entinostat (MS-275), durvalumab, valproic acid, idarubicin, eltrombopag, pevonedistat (MLN4924), eprenetapopt (APR-246), sabatolimab (MBG453), magrolimab (Hu5F9-G4), or tamibarotene (SY-1425)...While the approval of luspatercept and imetelstat for lower-risk patients provides a glimmer of hope, this track record of failure in higher-risk MDS is enough to make a prudent investor or senior pharmaceutical executive think twice before committing further resources to development in this difficult group of diseases...Nor is it because the existing therapies are so good that they're hard to beat, although the practice of giving a few cycles of azacitidine or decitabine in local clinics before referring a patient to a trial center has been an unfortunate barrier to accrual...In this session I will discuss some potential fixes for a few of these problems. But solutions to other barriers are less clear, and will require..."

Acute Myelogenous Leukemia • Hematological Malignancies • Multiple Myeloma • Myelodysplastic Syndrome • Oncology • FLT3 • TP53

Epigenetic modulation drives inflammatory responses in sarcoma (CIMT 2025) - "To investigate if H3K27ac expression influences inflammatory responses, the histone deacetylase 1-3 (HDAC) inhibitor Entinostat was used to induce H3K27ac expression in sarcoma tumors...Furthermore, genome wide H3K27ac levels may be used to predict survival in OS. In addition, H3K27ac levels are associated with immune-related signatures and could be explored to promote inflammatory responses in sarcoma."

Oncology • Osteosarcoma • Sarcoma • Solid Tumor • HDAC1 • VGLL3 • YAP1

Optimizing post-CDK4/6i strategies in HR+/HER2− metastatic breast cancer: A network meta-analysis of emerging therapies (ESMO-BC 2025) - "The findings showed that venetoclax plus fulvestrant demonstrated the strongest survival benefit among second-line and later HR+/HER2− MBC post-CDK4/6i therapies. Inavolisib and entinostat showed potential but require further validation. The limited efficacy of elacestrants suggests they may not be a preferred choice post-CDK4/6i."

Metastases • Retrospective data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • CDK4 • ER • HER-2

Predictive Oncology Reports First Quarter 2025 Financial Results and Provides Corporate Update (GlobeNewswire) - "Announced that, using publicly available datasets on drugs that have either been abandoned or discontinued by large pharmaceutical companies, Predictive has developed a registry of promising candidates that can potentially be repurposed for additional or alternative indications. Predictive’s initial screening approach on a small, curated cohort of abandoned drugs identified three compounds that warrant further exploration in new colon and breast tumor indications. Specifically, Afuresertib (breast), Alisertib (colon) and Entinosta (colon) demonstrated the highest proportion of hits within those two tumor types." "

Clinical • Breast Cancer • Colon Cancer • Colorectal Cancer

HISTONE DEACETYLASE INHIBITOR VORINOSTAT INDUCES R-LOOP-DEPENDENT CHANGES IN CHROMATIN ACCESSIBILITY AND ERYTHROID DIFFERENTIATION IN SF3B1-MUTATED ERYTHROBLASTS. (MDS 2025) - "Our aim is to explore R-loop-dependent transcriptional and epigenetic changes in MDS erythropoiesis.MethodsSF3B1MUT, SRSF2MUT and SFWTMDS erythroblasts were derived from BM CD34+progenitors and treated 24h with pan-HDACi (vorinostat, pracinostat) or selective HDAC(I/IV)i (entinostat). The impact of vorinostat on R-loop dynamics suggests an epigenetic regulation by histone acetylation of R-loop-dependent gene transcription. This may suggest testing low-dose vorinostat in transfusion-dependent SF3B1MUT-MDS patients resistant or non-eligible to luspatercept or ESAs."

Epigenetic controller • Hematological Malignancies • Myelodysplastic Syndrome • CD34 • CDKN1A • GATA1 • SF3B1 • SRSF2

Entinostat a Histone Deacetylase Inhibitor Improves Anti-tumor activity of Car-NK cells by sustaining CAR expression (IMMUNOLOGY 2025) - "In a mouse model of MM, ENT-treated CAR-NK cells exhibited superior tumor reduction, emphasizing their therapeutic efficacy. This study is the first to show that HDAC inhibitors can be used to restore CAR expression in CAR-NK cells through a promoter-dependent mechanism, enhancing anti-tumor activity in MM and warranting further clinical exploration.Keywords: Animals Human Rodent; Cells Natural Killer Cells; Molecules Cytokines; Techniques/Approaches Gene Therapy"

Epigenetic controller • IO biomarker • Gene Therapies • Hematological Malignancies • Multiple Myeloma • Oncology • SDC1

Combination of HDAC inhibition and cytokine enhances therapeutic HPV vaccine therapy. (PubMed, J Immunother Cancer) - "Together, these findings provide a rationale for the combination of HPV vaccine, NHS-IL12, and Entinostat in the clinical setting for patients with HPV16-associated malignancies."

IO biomarker • Journal • Head and Neck Cancer • Oncology • Solid Tumor • CD8 • IL12A

In vivo, ex vivo, and in vitro (2D and 3D) tumor models: Uses, strengths and limitations (AACR 2025) - "The 138582-377-R Merkel cell (PDX) treated with cediranib (6 mg/kg) & erlotinib (90 mg/kg) Q5D for 3 wks resulted in 80% decrease in tumor vol compared with controls & 80% cytotoxicity in complex spheroids from the same tumor. Less than 90% cytotoxicity was achieved in the complex spheroids in the estimated clinical Cmax concentration range of entinostat. The combination of ipatasertib (60 mg/kg) & selumetinib (20 mg/kg) administered twice per day for 2-rounds of 10 days was less effective in the 171881-019-R breast ca PDX and the 845751-090-R head & neck squamous ca PDX than would be predicted by the complex spheroid studies."

Preclinical • Oncology • Solid Tumor

Targeting the HLA-E-NKG2A axis in combination with MS-275 enhances NK cell-based immunotherapy against DMG. (PubMed, J Exp Clin Cancer Res) - "This study is the first to demonstrate that HDAC inhibition enhances NK cell-mediated cytotoxicity in DMG. Combining HDAC inhibition with NK cell therapy represents a promising therapeutic strategy for treating DMG by targeting NKG2A-HLA-E axis."

IO biomarker • Journal • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • HLA-E • KLRC1 • STAT3

Azacitidine and Entinostat in Treating Patients With Advanced Breast Cancer (clinicaltrials.gov) - P2 | N=58 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed

Trial completion • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • PGR

Epigenomic regulation of stemness contributes to the low immunogenicity of the most mutated human cancer. (PubMed, Cell Rep) - "Topical entinostat plus imiquimod immunotherapy blocked BCC development in mice. Collectively, our findings demonstrate that low BCC immunogenicity is associated with a stem-like quiescent program preserved in the tumor cells, which can be blocked to enable BCC immunotherapy."

IO biomarker • Journal • Tumor mutational burden • Basal Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Skin Cancer • FOXC1 • IRF1 • TMB

Ovarian cancer treatments: Using HSF1 and MYC gene amplification as a biomarker (AACR 2025) - "We show that loss of HSF1 and MYC decrease proliferation and colony formation ability of ovarian cancer cells using knockdown siRNAs and that the Volasertib and Entinostat inhibitors are more effective in treating ovarian cancers that carry amplifications of HSF1 and MYC than those with other driver amplifications. Work with both Volasertib and Entinostat aim to show that amplifications of oncogenes in high-grade serous ovarian cancer can be used as a biomarker for new treatment strategies in ovarian cancer."

Biomarker • Gynecologic Cancers • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • CCNE1 • HSF1 • KRAS • MYC

Chromatin remodeling enhances the anti-cancer effects of estrogen therapy in ER+ breast cancer (AACR 2025) - "We evaluated the effects of E2 and the histone deacetylase inhibitor (HDACi) entinostat in long-term estrogen-deprived (LTED) ER+ breast cancer cells, cells engineered to overexpress exogenous ER, and mice bearing endocrine-resistant patient-derived xenografts (PDX)...Efficacy is a result of increased DNA damage, elevated chromatin accessibility, treatment-induced ER activation, cell cycle stalling, and subsequent cell death. The novel combination of an HDACi and E2 has the potential to be an effective therapy for patients with endocrine-resistant ER+ breast cancer."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER

Epigenetic targeted therapies induce unique MHC-I epitopes identified by immunopeptidome analysis in low mutation-burden sarcomas (AACR 2025) - "We have been investigating the use of the hypomethylating agent decitabine (DAC) followed by histone deacetylase inhibitor entinostat (Enti) in our murine models of sarcoma to potentially increase the tumor immunogenicity. We identified epitopes from numerous proteins beyond CTAs indicating broad changes in antigen processing and antigenic peptides in the DAC+Enti treated cells. Further studies will validate the immunogenicity and ways to increase immune responses targeting these shared epigenetically regulated epitopes in sarcomas."

IO biomarker • Tumor mutational burden • Ewing Sarcoma • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • IFNG • KRAS • TMB

HMGA1 disrupts 3D genome architecture and chromatin looping to repress MHC-II genes and drive immune evasion (AACR 2025) - "Using artificial intelligence, we predicted that the histone deacetylase inhibitor, entinostat, targets HMGA1 networks...Single cell transcriptomics in patient samples demonstrate that HMGA1 correlates inversely with MHC-II repression, particularly in AML with bi-allelic TP53 mutations, demonstrating the relevance of this HMGA1 network in humans. Together, our data illuminate the HMGA1-MHC-II axis as a promising immunotherapeutic target to activate AP genes and trigger a T cell anti-tumor attack in MPN AML and potentially other cancers overexpressing HMGA1."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • HMGA1 • TP53

Exome-wide association study reveals 7 functional variants associated with ex-vivo drug response in acute myeloid leukemia patients. (PubMed, BMC Med Genomics) - "We identified exome-wide significant (p < 9.02 × 10- 7) associations for rs113985677 in CCIN with tamoxifen response, rs115400838 in TRMT5 with idelalisib response, rs11878277 in HDGFL2 with entinostat, and rs2229092 in LTA associated with vorinostat response. Additionally, a significant association of rs35704242 in NIBAN1 was associated with the combined response for nonchemotherapy medicines (p = 2.51 × 10- 8), and BI.2536, gefitinib, and belinostat were identified as the central traits. Our study represents the first EWAS to date on ex-vivo drug response in AML and reports 7 new associated loci that help to understand the anticancer drug response in AML patients."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Azacitidine and Entinostat in Treating Patients With Advanced Breast Cancer (clinicaltrials.gov) - P2 | N=58 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Mar 2025 ➔ Mar 2026

Trial completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • PGR

Dose-dependent dual effects of HDAC inhibitors on glial inflammatory response. (PubMed, Sci Rep) - "Specifically, the study evaluated the dose-dependent effects of two broad-spectrum HDACi, Trichostatin A (TSA) and Suberoylanilide Hydroxamic Acid (SAHA, Vorinostat), alongside selective inhibitors-MS-275 (Entinostat, class I), and MC1568 (class II)-on the expression and release of pro- and anti-inflammatory cytokines. This analysis revealed a dose-dependent alteration in gene expression and pathway enrichment associated with cytokine signaling and immune regulation (e.g., JAK-STAT). Altogether, these findings reveal insights on the subtle, dose- and context-dependent role of HDACi in modulating glia inflammation."

Journal • Inflammation • IL10 • IL1B • TNFA