- |||||||||| molibresib (GSK525762) / GSK, Jingzhuda (entinostat) / EOC Pharma, EddingPharm
Enrollment change, Trial withdrawal, Metastases: Testing a New Anti-cancer Drug Combination, Entinostat and GSK525762C, for Advanced and Refractory Solid Tumors and Lymphomas (clinicaltrials.gov) - Sep 24, 2020
P1, N=0, Withdrawn,
These results suggest that MS-275 alleviates postoperative cognitive dysfunction by reducing neuroinflammation in the hippocampus of rats via HDAC inhibition. N=49 --> 0 | Not yet recruiting --> Withdrawn
- |||||||||| Nutlin-3 / EMD Serono, entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax
Journal: The pseudo-caspase FLIP(L) regulates cell fate following p53 activation. (Pubmed Central) - Sep 20, 2020
Thus, even in the absence of caspase-8/10, FLIP(L) silencing promoted p53-induced apoptosis by enhancing PUMA expression. Thus, we report unexpected, therapeutically relevant roles for FLIP(L) in determining cell fate following p53 activation.
- |||||||||| everolimus / Generic mfg., sirolimus / Generic mfg.
Journal: Mouse tumor susceptibility genes identify drug combinations for multiple myeloma. (Pubmed Central) - Sep 16, 2020
The identification of MYC as a primary upstream regulator led to the identification of small molecule binders of the G-quadruplex structure that forms in the NHEIII region of the MYC promoter. These studies highlight the importance of identifying drug combinations which simultaneously upregulate tumor suppressors and downregulate oncogenes.
- |||||||||| Jingzhuda (entinostat) / EOC Pharma, EddingPharm
Enrollment closed, Metastases: High Dose IL 2 and Entinostat in RCC (clinicaltrials.gov) - Sep 14, 2020
P2, N=46, Active, not recruiting,
These studies highlight the importance of identifying drug combinations which simultaneously upregulate tumor suppressors and downregulate oncogenes. Recruiting --> Active, not recruiting
- |||||||||| Jingzhuda (entinostat) / EOC Pharma, EddingPharm, Opdivo (nivolumab) / BMS, Yervoy (ipilimumab) / BMS
Enrollment closed, Trial primary completion date, Combination therapy: Study of Entinostat With Nivolumab Plus Ipilimumab in Previously Treated Renal Cell Carcinoma (clinicaltrials.gov) - Sep 13, 2020
P2, N=53, Active, not recruiting,
Recruiting --> Active, not recruiting Recruiting --> Active, not recruiting | Trial primary completion date: Aug 2020 --> Aug 2021
- |||||||||| axatilimab (SNDX-6352) / Syndax Pharma, Incyte
Enrollment closed, Trial completion date, Trial primary completion date, Combination therapy, Monotherapy, Metastases: A Phase 1 Study to Investigate SNDX-6352 Alone or in Combination With Durvalumab in Patients With Solid Tumors (clinicaltrials.gov) - Sep 10, 2020
P1, N=45, Active, not recruiting,
Recruiting --> Active, not recruiting | Trial primary completion date: Aug 2020 --> Aug 2021 Recruiting --> Active, not recruiting | Trial completion date: Feb 2019 --> Feb 2021 | Trial primary completion date: Feb 2019 --> Feb 2021
- |||||||||| entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax
Journal: The Histone Deacetylase Inhibitor Entinostat/Syndax 275 in Osteosarcoma. (Pubmed Central) - Sep 1, 2020
Agents such as gemcitabine and the HDAC inhibitor, entinostat/Syndax 275, have been shown to upregulate Fas expression on OS cells, potentially leading to decreased OS pulmonary metastasis and improved outcome. Clinical trials are in development to evaluate this combination as a potential treatment option for patients with refractory OS.
- |||||||||| cisplatin / Generic mfg., entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax
Journal: MS-275 combined with cisplatin exerts synergistic antitumor effects in human esophageal squamous cell carcinoma cells. (Pubmed Central) - Aug 18, 2020
Further study displayed that MS-275 combined with DDP suppressed Wnt/β-catenin signaling in EC9706 cells and xenografts. These results indicate that MS-275 combined with DDP exerts synergistic antitumor effects by enhancing the chemosensitivity of EC9706 cells to DDP, which may be a potential therapeutic strategy for the treatment of patients with ESCC.
- |||||||||| entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax, rocilinostat (ACY-1215) / Regenacy, BMS
Clinical, Journal, Myeloid-derived suppressor cells: Selective targeting of different populations of myeloid-derived suppressor cells by histone deacetylase inhibitors. (Pubmed Central) - Aug 18, 2020
However, combination of entinostat and ricolinostat abrogated suppressive activity of both populations of MDSC and substantially delayed tumor progression. Thus, inactivation of MDSC required targeting of both major subsets of these cells via inhibitors of class I and class II HDAC.
- |||||||||| Imfinzi (durvalumab) / AstraZeneca
Trial completion date, Trial primary completion date, Combination therapy: Durvalumab and SNDX-6532 Following Chemo or Radio-Embolization for Patients With Intrahepatic Cholangiocarcinoma (clinicaltrials.gov) - Jul 13, 2020
P2, N=30, Not yet recruiting,
A new orally bioavailable Menin-MLL inhibitor (VTP-50469) appears to promote their differentiation through direct effects on the HOX cofactor MEIS1, paving the way for clinical trials. Trial completion date: Jun 2024 --> Sep 2024 | Trial primary completion date: Jun 2024 --> Sep 2024
- |||||||||| Biomarker, Journal, Combination therapy, IO biomarker: Histone deacetylase inhibition in combination with MEK or BCL-2 inhibition in multiple myeloma. (Pubmed Central) - Jul 8, 2020
Furthermore, these drug combinations effectively killed plasma cells from myeloma patients ex vivo. Given the preponderance of RAS/RAF mutations, and the fact that ABT-199 has demonstrated clinical efficacy in relapsed/refractory multiple myeloma, these drug combinations hold promise as biomarker-driven therapies.
- |||||||||| Nerlynx (neratinib) / Puma, Knight Therap, Pierre Fabre, entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax
Biomarker, Journal, PD(L)-1 Biomarker, IO Biomarker: Neratinib and entinostat combine to rapidly reduce the expression of K-RAS, N-RAS, Gα and Gα and kill uveal melanoma cells. (Pubmed Central) - Jul 7, 2020
Our data demonstrate that [neratinib + entinostat] down-regulates oncogenic RAS and the two key oncogenic drivers present in most uveal melanoma patients and causes a multifactorial form of killing via mitochondrial dysfunction and toxic autophagy. Abbreviations: ERK: extracellular regulated kinase; PI3K: phosphatidyl inositol 3 kinase; ca: constitutively active; dn: dominant negative; ER: endoplasmic reticulum; AIF: apoptosis inducing factor; AMPK: AMP-dependent protein kinase; mTOR: mammalian target of rapamycin; JAK: Janus Kinase; STAT: Signal Transducers and Activators of Transcription; MAPK: mitogen activated protein kinase; PTEN: phosphatase and tensin homologue on chromosome ten; ROS: reactive oxygen species; CMV: empty vector plasmid or virus; si: small interfering; SCR: scrambled; IP: immunoprecipitation; VEH: vehicle; HDAC: histone deacetylase.
- |||||||||| entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax
[VIRTUAL] Dual LSD1/HDAC inhibition accelerates skin wound healing () - Jul 1, 2020 - Abstract #SID2020SID_667;
Corin is a synthetic hybrid agent derived from the HDAC inhibitor (MS-275) and LSD1 inhibitor...qRT-PCR gene expression analysis of corin-treated keratinocytes showed significant upregulation of the genes associated with cell migration, such as CD24, EPHB2, ITGAX, PTGS, SCT1, SERPINB2, SERPINE1, and SLPI. In summary, our study demonstrates that dual HDAC1 and LSD1 inhibition by corin promotes acetylation of H3K9 and skin wound healing via stimulation of migratory activities of epidermal keratinocytes.
- |||||||||| entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax, tranylcypromine / GSK, Generic mfg.
[VIRTUAL] Dual HDAC and LSD1 inhibition as a novel strategy to overcome BRAF inhibitor resistance () - Jul 1, 2020 - Abstract #SID2020SID_553;
Gene expression analysis revealed that Corin is a potent inducer of tumor suppressor genes, many of which have been observed to be epigenetically silenced in cancer. This novel, dual action inhibition presents a specific and potent approach to targeting epigenetic mechanisms to overcome acquired BRAFi resistance in melanoma and may serve as a model for overcoming intrinsic and acquired therapeutic resistance in other cancers as well.
- |||||||||| sepantronium bromide (YM155) / Astellas, entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax
Journal: MS-275 potentiates the effect of YM-155 in lung adenocarcinoma via survivin downregulation induced by miR-138 and miR-195. (Pubmed Central) - Jun 29, 2020
This novel, dual action inhibition presents a specific and potent approach to targeting epigenetic mechanisms to overcome acquired BRAFi resistance in melanoma and may serve as a model for overcoming intrinsic and acquired therapeutic resistance in other cancers as well. For the first time, we report the synergistic effective of MS-275 and YM-155 and suggest a new direction for the future application of YM-155.
- |||||||||| entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax
Journal: HDAC inhibitors impair Fshb subunit expression in murine gonadotrope cells. (Pubmed Central) - Jun 19, 2020
Similar results were obtained with the class I specific HDAC inhibitor, entinostat, whereas two class II specific inhibitors, MC1568 and TMP269, had no effects on Fshb expression. Collectively, these data suggest that class I HDACs are positive, not negative, regulators of Fshb expression in vitro and that, contrary to earlier reports, GnRH may not stimulate Fshb by inhibiting HDAC-mediated repression of the gene.
- |||||||||| Keytruda (pembrolizumab) / Merck (MSD), Jingzhuda (entinostat) / EOC Pharma, EddingPharm
Trial completion date, Trial primary completion date, Combination therapy, Epigenetic controller: Testing the Safety and Efficacy of the Combination of the Antibody Pembrolizumab and Entinostat in Patients With Myelodysplastic Syndrome Who Are Not Responding to Hypomethylating Agents (clinicaltrials.gov) - Jun 17, 2020
P1b, N=27, Recruiting,
Collectively, these data suggest that class I HDACs are positive, not negative, regulators of Fshb expression in vitro and that, contrary to earlier reports, GnRH may not stimulate Fshb by inhibiting HDAC-mediated repression of the gene. Trial completion date: Jun 2020 --> Jun 2021 | Trial primary completion date: Jun 2020 --> Jun 2021
- |||||||||| entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax
Journal: MS-275 induces hepatic FGF21 expression via H3K18ac-mediated CREBH signal. (Pubmed Central) - Jun 8, 2020
As a proved transcription factor of FGF21, the expression of CREBH was initiated by MS-275, with increased Histone H3 Lysine 18 acetylation(H3K18ac) signals and hepatocyte nuclear factor 4 alpha (HNF-4α) recruitment in CREBH promoter. Adenovirus-mediated knockdown of CREBH abolished MS-275-induced hepatic FGF21 and lipid metabolism-related gene expressions.These results suggest that MS-275 induces hepatic FGF21 by H3K18ac-mediated CREBH expression.
- |||||||||| entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax
Journal: Entinostat augments NK cell functions via epigenetic upregulation of IFIT1-STING-STAT4 pathway. (Pubmed Central) - Jun 6, 2020
Corresponding transcriptome analysis revealed enrichment of IRF1 and STAT4 and gene sets responsible for NK cell-mediated IFN-γ production and cytotoxicity, respectively. Our results show a novel mechanism by which entinostat initiates an IFIT1-STING-mediated potentiation of STAT4 via IRF1 to augment NK cell-mediated anti-tumor responses.
- |||||||||| entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax
Journal: Inflammation-mediated deacetylation of the ribonuclease 1 promoter via histone deacetylase 2 in endothelial cells. (Pubmed Central) - Jun 5, 2020
Inhibition of histone deacetylase (HDAC) 1, 2, and 3 by the specific class I HDAC inhibitor MS275 abolished the TNF-α- or IL-1β-mediated effect on the mRNA and chromatin levels of RNase1...Thus, proinflammatory stimulation induced recruitment of HDAC2 to attenuate histone acetylation at the RNASE1 promoter site. Consequently, treatment with HDAC inhibitors may provide a new therapeutic strategy to stabilize vascular homeostasis in the context of inflammation by preventing RNase1 down-regulation in ECs.-Bedenbender, K., Scheller, N., Fischer, S., Leiting, S., Preissner, K. T., Schmeck, B. T., Vollmeister, E. Inflammation-mediated deacetylation of the ribonuclease 1 promoter via histone deacetylase 2 in endothelial cells.
- |||||||||| Jingzhuda (entinostat) / EOC Pharma, EddingPharm, Lynparza (olaparib) / Merck (MSD), AstraZeneca
Enrollment open: Olaparib and Entinostat in Patients With Recurrent, Platinum-Refractory, Resistant Ovarian, Primary Peritoneal, Fallopian Tube Cancers (clinicaltrials.gov) - Jun 5, 2020
P1/2, N=73, Recruiting,
Consequently, treatment with HDAC inhibitors may provide a new therapeutic strategy to stabilize vascular homeostasis in the context of inflammation by preventing RNase1 down-regulation in ECs.-Bedenbender, K., Scheller, N., Fischer, S., Leiting, S., Preissner, K. T., Schmeck, B. T., Vollmeister, E. Inflammation-mediated deacetylation of the ribonuclease 1 promoter via histone deacetylase 2 in endothelial cells. Suspended --> Recruiting
- |||||||||| entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax
Biomarker, Journal, BRCA Biomarker: MAPK pathway suppression unmasks latent DNA repair defects and confers a chemical synthetic vulnerability in BRAF, NRAS, and NF1 mutant melanomas. (Pubmed Central) - May 31, 2020
Specifically, we show that entinostat dramatically enhances tumor regression when combined with BRAF/MEK inhibitors, in both models that are sensitive or relatively resistant to these agents...BRAF/MEK inhibitors enhance these defects by suppressing homologous recombination genes, inducing a BRCA-like state; however, entinostat addition triggers the concomitant suppression of NHEJ genes, resulting in a chemical synthetic lethality caused by excessive DNA damage. Together these studies identify melanomas with latent DNA repair defects, describe a promising drug combination that capitalizes on these defects, and reveal a tractable therapeutic biomarker.
- |||||||||| entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax
Journal: Class I HDAC inhibitors enhance YB-1 acetylation and oxidative stress to block sarcoma metastasis. (Pubmed Central) - May 23, 2020
MS-275 dramatically reduces sarcoma metastasis in vivo, but an MS-275-resistant YB-1K81-to-alanine mutant restores metastatic capacity and NRF2, HIF1α, and G3BP1 synthesis in MS-275-treated mice. These studies describe a novel function for MS-275 through enhanced YB-1 acetylation, thus inhibiting YB-1 translational control of key cytoprotective factors and its pro-metastatic activity.
- |||||||||| entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax
Entinostat induces PARPi sensitivity across multiple ovarian cancer models (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_706;
These studies describe a novel function for MS-275 through enhanced YB-1 acetylation, thus inhibiting YB-1 translational control of key cytoprotective factors and its pro-metastatic activity. Entinostat in combination with Olaparib decreased cell proliferation, increased DNA damage, induced HR deficiency in vitro, reduced tumor burden, decreased Ki67 in xenograft mouse model, and improved survival of HGSOC derived PDX mice, thereby potentially sensitizing homologous recombination proficient ovarian cancer to PARPi across multiple models.
- |||||||||| Birinapant enhances gemcitabine’s anti-tumor efficacy in triple-negative breast cancer by inducing intrinsic pathway-dependent apoptosis (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_1850;
Here, we assessed whether birinapant synergizes with commonly used anti-cancer drugs, including entinostat (class I histone deacetylase inhibitor), cisplatin, paclitaxel, voxtalisib (PI3K inhibitor), dasatinib (Src inhibitor), everolimus (mTOR inhibitor), and gemcitabine, in triple-negative breast cancer (TNBC). Our findings demonstrate the therapeutic potential of birinapant for enhancing the anti-tumor efficacy of gemcitabine in TNBC by targeting the IAP family of proteins.
- |||||||||| Nutlin-3 / EMD Serono, entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax
FLIP(L) determines colon cancer cell fate following p53 activation (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_1837;
This is mediated through two previously undescribed mechanisms, preventing apoptosis by a ligand-independent TRAIL-R2 complex and by suppressing expression of pro-apoptotic PUMA. Which, importantly imposes a critical dependence on FLIP(L) which can be overcome through combinations with class-I HDAC inhibitors such as Entinostat.
- |||||||||| Jingzhuda (entinostat) / EOC Pharma, EddingPharm, Lynparza (olaparib) / Merck (MSD), AstraZeneca
Trial completion date, Trial suspension, Trial primary completion date: Olaparib and Entinostat in Patients With Recurrent, Platinum-Refractory, Resistant Ovarian, Primary Peritoneal, Fallopian Tube Cancers (clinicaltrials.gov) - May 14, 2020
P1/2, N=73, Suspended,
Besides, the mechanism of differentiation of these compounds is due, at least in part, to the acetylation of non-histone epigenetic proteins, which are key in the myeloid differentiation. Trial completion date: Mar 2025 --> Sep 2025 | Not yet recruiting --> Suspended | Trial primary completion date: Mar 2023 --> Sep 2023
- |||||||||| entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax Pharma
Preclinical, Journal: Preclinical rationale for entinostat in embryonal rhabdomyosarcoma. (Pubmed Central) - May 7, 2020
Our results suggest that the targeting class I HDACs may provide a therapeutic benefit for selected patients with eRMS. ENT's preclinical in vivo efficacy makes ENT a rational drug candidate in a phase II clinical trial for eRMS.
- |||||||||| entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax, Tecentriq (atezolizumab) / Roche
[VIRTUAL] Results of ENCORE 602 (TRIO025), a phase II, randomized, placebo-controlled, double-blinded, multicenter study of atezolizumab with or without entinostat in patients with advanced triple-negative breast cancer (aTNBC). (Poster Board 99) - Apr 29, 2020 - Abstract #ASCO2020ASCO_1739;
P1b
with previously treated aTNBC, median PFS was not prolonged when ENT was added to ATEZO compared to ATEZO and placebo, and the combination resulted in greater toxicity. Research Funding: Syndax Pharmaceutical Inc.
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