- |||||||||| Mekinist (trametinib) / Novartis, entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma, REC-4881 / Recursion Pharma
Journal: Combining HDAC and MEK Inhibitors with Radiation against Glioblastoma-Derived Spheres. (Pubmed Central) - Apr 12, 2022
Finally, we showed that the combined treatment with radiation was more effective at reducing the GSLC markers compared to the standard treatment of temozolomide and radiation. These results suggest that combining HDAC and MEK inhibition with radiation may offer a new strategy to improve the treatment of glioblastoma.
- |||||||||| entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
Preclinical, Journal: Beneficial and Sexually Dimorphic Response to Combined HDAC Inhibitor Valproate and AMPK/SIRT1 Pathway Activator Resveratrol in the Treatment of ALS Mice. (Pubmed Central) - Apr 9, 2022
Epigenetic modulation in the acetylation state of NF-kB RelA and the histone 3 (H3) protein, involved in the development of neurodegeneration, is a drugable target for the class-I histone deacetylases (HDAC) inhibitors, entinostat or valproate, and the AMP-activated kinase (AMPK)-sirtuin 1 pathway activator, resveratrol...Only minor beneficial effects were produced in the latter stage in males. Overall, this study shows a beneficial and sexually dimorphic response to valproate and resveratrol treatment in ALS mice.
- |||||||||| entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
Journal: Mechanistic insights into p53-regulated cytotoxicity of combined entinostat and irinotecan against colorectal cancer cells. (Pubmed Central) - Apr 8, 2022
This specifically relies on the C-terminal acetylation of p53 by CREB binding protein (CBP)/p300 and the presence of C-terminally acetylated p53 in complex with the pro-apoptotic BCL2 antagonist/killer (BAK) protein. This control of C-terminal acetylation by HDACs can mechanistically explain why combinations of irinotecan and entinostat represent clinically tractable agents for the therapy of p53-proficient CRC.
- |||||||||| entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma, Lynparza (olaparib) / Merck (MSD), AstraZeneca
Entinostat Restores Responsiveness to Olaparib in ID8TP53null and ID8TP53null/BRCA2null Mouse Ovarian Cancer Cell Lines. () - Apr 6, 2022 - Abstract #SRI2022SRI_494;
Entinostat restores responsiveness to olaparib in ID8 TP53 null HR proficient mouse ovarian cancer cells that molecularly resemble high-grade serous ovarian carcinoma. These results suggest this drug combination can overcome intrinsic resistance to PARPi and provide additional preclinical support for clinical investigation of this combination for the treatment of HR proficient ovarian cancer.
- |||||||||| Farydak (panobinostat) / Secura Bio, entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
Preclinical, Journal, Epigenetic controller: The Effect of Histone Deacetylase Inhibitors Panobinostat or Entinostat on Motor Recovery in Mice After Ischemic Stroke. (Pubmed Central) - Apr 5, 2022
This was accompanied by negligible changes of parvalbumin-positive neurons recorded in AGm and comparable infarct volumes among experimental groups, while dose-dependent increase in acetylated histone 3 was observed in peri-infarct cortex of drug-treated animals. Our observations suggest that add-on panobinostat or entinostat therapy coupled with limited physical rehabilitation is unlikely to offer therapeutic modality for stroke survivors who have motor dysfunction.
- |||||||||| Jingzhuda (entinostat) / EOC Pharma, EddingPharm, Lynparza (olaparib) / Merck (MSD), AstraZeneca
Enrollment change, Trial completion date, Trial termination, Trial primary completion date: Olaparib and Entinostat in Patients With Recurrent, Platinum-Refractory, Resistant Ovarian, Primary Peritoneal, Fallopian Tube Cancers (clinicaltrials.gov) - Apr 4, 2022
P1/2, N=3, Terminated,
This finding might suggest the usefulness of pan-HDAC inhibitors in clinical treatment in combination with immune checkpoint inhibitors. N=73 --> 3 | Trial completion date: Sep 2026 --> Feb 2022 | Recruiting --> Terminated | Trial primary completion date: Sep 2024 --> Feb 2022; Change in participant landscape and other treatment availability
- |||||||||| Avastin (bevacizumab) / Roche, Jingzhuda (entinostat) / EOC Pharma, EddingPharm, Tecentriq (atezolizumab) / Roche
Enrollment change, Trial completion date, Trial suspension, Trial primary completion date, Combination therapy, Metastases: Atezolizumab in Combination With Entinostat and Bevacizumab in Patients With Advanced Renal Cell Carcinoma (clinicaltrials.gov) - Mar 14, 2022
P1/2, N=72, Suspended,
Despite no immediate effect of entinostat on PR in this short-term study, lessons learned can inform future window and treatment trials. N=29 --> 72 | Trial completion date: Dec 2022 --> Dec 2023 | Active, not recruiting --> Suspended | Trial primary completion date: Dec 2021 --> Dec 2022
- |||||||||| Keytruda (pembrolizumab) / Merck (MSD), Jingzhuda (entinostat) / EOC Pharma, EddingPharm
Trial completion date, Trial primary completion date, Combination therapy: Combination Therapy With Entinostat and Pembrolizumab in Relapsed and Refractory Lymphomas (clinicaltrials.gov) - Mar 10, 2022
P2, N=47, Recruiting,
A novel ARlncRNA signature for LUAD prognostic prediction was constructed, which had better efficacy than the TNM stage and used to propose potential therapeutic regimens for LUAD patients. Trial completion date: Jun 2022 --> Jun 2023 | Trial primary completion date: Jun 2022 --> Jun 2023
- |||||||||| Isoform-selective HDAC inhibition up-regulates CD26 expression on multiple myeloma cells and augments cytotoxic efficacy by humanized monoclonal antibody (E-Poster Website) - Mar 9, 2022 - Abstract #AACR2022AACR_6933;
Although the cell surface expression of CD26 was relatively low or not detected on 5 MM cell lines (KMS26, KMS27, KMS28, KMS11, RPMI8226), the increased expression in CD26 levels was detectable within 24 h of the treatment with HDAC1i; FK228, HDAC3i; BG45, MS-275, RG2833 or HDAC6i; nexturastat A, tubastatin A, ACY-1215 as well as broad HDACi; LBH-589, SAHA... Combination with isoform-selective HDACi not only shows anti-MM activity but supports as immunopotentiators by sensitizing CD26neg MM cells to CD26mAb and augment its cytotoxicity against MM cells.
- |||||||||| entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma, Istodax (romidepsin) / Astellas, BMS
Targeting the (epigenetic) expression program of primary Ewing sarcoma (Section 15) - Mar 9, 2022 - Abstract #AACR2022AACR_6325;
Combination with isoform-selective HDACi not only shows anti-MM activity but supports as immunopotentiators by sensitizing CD26neg MM cells to CD26mAb and augment its cytotoxicity against MM cells. Spheroid growth culture of primary EwS is an excellent tool to preclinically evaluate potentially effective targeted therapeutic approaches on individual patient material.
- |||||||||| Menin inhibitor-based combinations to improve efficacy and overcome resistance in AML (Section 26) - Mar 9, 2022 - Abstract #AACR2022AACR_5976;
Co-treatment with SNDX-5613 and venetoclax or OTX015 compared to each drug or vehicle control, administered orally for 3 to 4 weeks to NSG mice engrafted with either MOLM13-GFP/Luciferase xenograft or with PD NPM1c and mtFLT3 AML xenograft, caused significantly greater reduction in AML burden and increased overall survival without weight loss or other toxicities (p < 0.005). These preclinical findings highlight novel MI-based combinations exhibiting superior in vitro and in vivo anti-AML efficacy against AML cells harboring MLL1-FP or NPM1c that are sensitive to MI or the MITR cells.
- |||||||||| entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma, Lynparza (olaparib) / Merck (MSD), AstraZeneca
Entinostat restores responsiveness to Olaparib in ID8 TP53 null and ID8 TP53 null/BRCA2 null mouse ovarian cancer cell lines (Section 5) - Mar 9, 2022 - Abstract #AACR2022AACR_3525;
Also preliminarily, there was increased number of γH2AX foci in combination treatment compared to controls and each drug alone.Entinostat restores responsiveness to olaparib in ID8 TP53 null HR proficient mouse ovarian cancer cells that molecularly resemble high-grade serous ovarian carcinoma. These results suggest this drug combination can overcome intrinsic resistance to PARPi and provide additional preclinical support for clinical investigation of this combination for the treatment of HR proficient ovarian cancer.
- |||||||||| entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
Class 1 HDAC inhibition induces antitumor immunity by NF-kB-mediated enhanced metabolic fitness and generation of unique effector function enriched memory CD8 T cell subtype (E-Poster Website) - Mar 9, 2022 - Abstract #AACR2022AACR_2488;
Therefore, we aimed to understand the effect of HDAC inhibition (HDACi) on CD8 T cells phenotype and functionality by using Entinostat (ENT), a class I HDAC (HDAC1 and 3) inhibitor...Next, flow cytometry and immunofluorescence analysis showed that although ENT does not increase total NF-κB levels in CD8 T cells, it enhances its binding to the chromatin due to enhanced gene accessibility. This research highlights the significance of epigenetic modulation in enhancing the immune-mediated anti-tumor effects and provide fundamental understanding of the mechanism of action of HDAC inhibition in CD8 T cells.
- |||||||||| Zolinza (vorinostat) / Merck (MSD), entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
Journal, Epigenetic controller: Synthesis and biological evaluation of aminobenzamides containing purine moiety as class I histone deacetylases inhibitors. (Pubmed Central) - Mar 8, 2022
Pulse exposure test of western blot assay demonstrated that 9a, 9d induced histone acetylation in a similar manner to MS-275. Further biological validation demonstrated that 9d prevented cell transition from G1 phase to S phase by reducing Cyclin D1, CDK2 and lifting p21, induced early apoptosis by upregulating BAX and downregulating Bcl-2 in HCT-116 cells.
- |||||||||| entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
Journal, Epigenetic controller: Systemic study of selected HDAC inhibitors in cardiac complications associated with cancer cachexia. (Pubmed Central) - Mar 5, 2022
Entinostat showed promising results by attenuating the cardiac complications, MC1568 treatment further exacerbated the cardiac complications while non-conclusive effect were recorded after treatment with sodium butyrate. Further, this study will be helpful in evaluating other HDAC inhibitors for potential in cardiac complications associated with cancer cachexia.
- |||||||||| mocetinostat (MGCD0103) / Mirati, Otsuka, entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma, volasertib (BI 6727) / Oncoheroes, Notable Labs
Journal: A Cell-Based Screen Identifies HDAC Inhibitors as Activators of RIG-I Signaling. (Pubmed Central) - Mar 4, 2022
Combination treatment of tumor cell lines with Entinostat increased RIG-I induced cell death in a mammary carcinoma cell line that is resistant to either Entinostat or RIG-I agonist alone. Taken together, our data indicates an unexpected role for HDAC1,-3 inhibitors in enhancing RIG-I signaling and highlight potential opportunities for therapeutic combinations.
- |||||||||| Clinical, Review, Journal, Combination therapy: Targeting cancer epigenetic pathways with small-molecule compounds: Therapeutic efficacy and combination therapies. (Pubmed Central) - Feb 26, 2022
However, lack of potent, selective, and clinically tractable small-molecule compounds makes the strategy to target cancer epigenetic pathways still challenging. Therefore, this review focuses on epigenetic pathways, small molecule inhibitors targeting DNA methyltransferase (DNMT) and small molecule inhibitors targeting histone modification (the main regulatory targets are histone acetyltransferases (HAT), histone deacetylases (HDACs) and histone methyltransferases (HMTS)), as well as the combination strategies of the existing epigenetic therapeutic drugs and more new therapies to improve the efficacy, which will shed light on a new clue on discovery of more small-molecule drugs targeting cancer epigenetic pathways as promising strategies in the future.
- |||||||||| axatilamab (SNDX-6352) / Syndax Pharma, Incyte
Importance of patient education in the utilization of Lee Symptom Scales in patients with cGVHD for analysis of symptom control (Anaheim Convention Center - Learning Hall: Poster Pavilion) - Feb 25, 2022 - Abstract #ONS2022ONS_426;
Applying these methods decreased questionnaire fatigue and led to the collection of a robust data set illustrating a 7-point improvement in 50% (n=19/38) of pts (Fig 1) and contributing to axatilimab's continued development. AGAVE-201 and other studies in cGVHD will continue to utilize the original or modified LSS to assess symptom control, highlighting the importance of patient education in the utilization of these tools.
- |||||||||| VTP-50469 / Syndax Pharma
Journal: The Menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML. (Pubmed Central) - Feb 24, 2022
Using mouse leukemia cell lines driven by NUP98-HOXA9 and NUP98-JARID1A fusion oncoproteins, we demonstrate that NUP98-fusion-driven leukemia is sensitive to the menin-MLL1 inhibitor VTP50469, with an IC50 similar to what we have previously reported for MLL-rearranged and NPM1c leukemia cells...Gene expression analysis revealed that Menin-MLL1 inhibition simultaneously suppresses a pro-leukemogenic gene expression program, including downregulation of the HOXA cluster, and upregulates tissue-specific markers of differentiation. These preclinical results suggest that Menin-MLL1 inhibition may represent a rational, targeted therapy for patients with NUP98-rearranged leukemias.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, SNDX-5613 / Syndax Pharma, Verzenio (abemaciclib) / Eli Lilly
Journal, IO biomarker: Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c). (Pubmed Central) - Feb 23, 2022
Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1.
- |||||||||| entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
Clinical, P1 data, Clinical Trial,Phase I, Journal, Monotherapy: Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer. (Pubmed Central) - Feb 22, 2022
P1
Entinostat monotherapy and combined entinostat/exemestane were well tolerated in Japanese patients, with no additional safety concerns compared with previous reports. The correlation between pharmacokinetics and Ac-K in peripheral blood CD19+ B cells, and also T-cell activation markers, merits further investigation.
- |||||||||| entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
Journal: A Prognostic Model for Acute Myeloid Leukemia Based on IL-2/STAT5 Pathway-Related Genes. (Pubmed Central) - Feb 22, 2022
Among the five drugs, MS.275, a known HDAC inhibitor, selectively suppressed the proliferation of cancer cells with high STAT5 phosphorylation levels in vitro. Taken together, the data indicate that the STAT5-associated signature is a reliable prognostic model that can be used to optimize prognostic stratification and guide personalized AML treatments.
- |||||||||| CRA-026440 / Quest Diagnostics, entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma, Istodax (romidepsin) / Astellas, BMS
Journal, Epigenetic controller: Class I histone deacetylases (HDAC) critically contribute to Ewing sarcoma pathogenesis. (Pubmed Central) - Feb 19, 2022
Taken together, the data indicate that the STAT5-associated signature is a reliable prognostic model that can be used to optimize prognostic stratification and guide personalized AML treatments. Class I HDAC proteins seem to be important mediators of the pathognomonic EWS-ETS-mediated transcription program in EwS and in combination therapy, co-treatment with HDACi is an interesting new treatment opportunity for this malignant disease.
- |||||||||| Xtandi (enzalutamide) / Pfizer, Astellas, Bausch Health, entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
Journal: Dual-function antiandrogen/HDACi hybrids based on enzalutamide and entinostat. (Pubmed Central) - Feb 17, 2022
Antiproliferative assays showed that hybrids bearing o-aminoanilide-based HDACi motifs outperformed hydroxamic acid based HDACi's. The hybrids demonstrated selectivity for epithelial cell lines vs. stromal cell lines, suggesting a potentially useful therapeutic window.
- |||||||||| cisplatin / Generic mfg., azacitidine / Generic mfg.
Clinical, Journal: Prognostic Impact of Schlafen 11 in Bladder Cancer Patients Treated with Platinum-based Chemotherapy. (Pubmed Central) - Feb 12, 2022
The epigenetic modifying drugs 5-azacytidine and entinostat restored SLFN11 expression and re-sensitized cells to cisplatin and carboplatin in SLFN11-negative BC cell lines. We conclude that SLFN11 is a predictive biomarker for BC patients who undergo platinum-based chemotherapy and that the combination of epigenetic modifiers could rescue refractory BC patients to platinum derivatives by reactivating SLFN11 expression.
- |||||||||| tolinapant (ASTX660) / Otsuka
Clinical, Journal: Clinical Positioning of the IAP Antagonist Tolinapant (ASTX660) in Colorectal Cancer. (Pubmed Central) - Feb 11, 2022
Further analyses revealed that caspase-8 knockout RIPK3-positive colorectal cancer models were sensitive to tolinapant-induced necroptosis, an effect that could be exploited in caspase-8-proficient models using the clinically relevant caspase inhibitor emricasan. Our study provides evidence for immediate clinical exploration of tolinapant in combination with FOLFOX in poor prognosis MSS colorectal cancer with elevated cIAP1/2 expression.
- |||||||||| Zolinza (vorinostat) / Merck (MSD), entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
Preclinical, Journal: A multiparametric pharmacogenomic strategy for drug repositioning predicts therapeutic efficacy for glioblastoma cell lines. (Pubmed Central) - Feb 5, 2022
Our studies suggest that reversal of glioblastoma disease signature correlates with drug potency for various GBM subtypes. This multiparametric approach may set the foundation for an early-phase personalized -omics clinical trial for glioblastoma by effectively identifying drugs that are capable of reversing the disease signature and have favorable pharmacokinetic and safety profiles.
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