- |||||||||| Xtandi (enzalutamide) / Pfizer, Astellas, MG132 / Jilin University, Dorothy M. Davis Heart and Lung Research Institute, entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax Pharma
Journal, PARP Biomarker: Tumor Suppressive Maspin-Sensitized Prostate Cancer to Drug Treatment Through Negative Regulating Androgen Receptor Expression. (Pubmed Central) - Nov 18, 2020
Finally, maspin-mediated repression of AR was induced by treatment of MS-275, which promoted enzalutamide treatment efficacy with decrease of prostate-specific antigen (PSA) expression in LNCaP and 22RV1 cells. Taken together, the data not only demonstrated maspin-mediated repression of AR to augment drug anti-tumor activity but also provided in-depth support for combination of HDAC inhibitors with AR antagonist in CaP therapy.
- |||||||||| Zolinza (vorinostat) / Merck (MSD), Farydak (panobinostat) / Novartis, entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax Pharma
Review, Journal, IO Biomarker: Histone Deacetylase Inhibition in Non-small Cell Lung Cancer: Hype or Hope? (Pubmed Central) - Nov 11, 2020
In this paper, we review the available preclinical and clinical evidence for the use of HDACi in NSCLC. We also review the challenges precluding widespread clinical utility of HDACi as a cancer therapy and future directions.
- |||||||||| Leustatin (cladribine) / J&J
[VIRTUAL] Novel Combination Drug Regimens Using Hypomethylating Agents in Treatment of Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia () - Nov 5, 2020 - Abstract #ASH2020ASH_4981;
In addition, three studies compared outcomes of CDR involving decitabine with all trans retinoic acid (ATRA)(n=93, ORR=21.9% vs 13.5%, p=0.06; mOS= 8.2 m vs 5.1 m, p=0.006) or talacotuzumab (CR/CRi= 15% vs 11%, p=0.44; mOS= 5.36 m vs 7.26 m, p=0.78) or bortezomib (CR/CRi= 39% vs 38%, p=0.91, mOS=9.3 m vs 8.9,p=0.18) to decitabine alone...Drugs included midostaurin (n= 88 , CR/CRi=25-29% mOS= 6-8 m) and pracinostat (n= 50, CR/CRi =46% mOS=19.1 m), In addition, two studies compared outcomes using CDR involving AZA with panobinostat (n=22, CR= 22.4 vs 30.8%, OS at 1 year = 60% vs 70%) or entinostat (n=18, ORR= 0% vs 16.6%, mOS=6 m vs 13 m) to AZA alone...The above listed efficacious CDR involving decitabine in phase I/II studies need to be evaluated in large, randomized trials to assess for definitive benefit. If proven efficacious in larger studies, they could serve as additional first line CDR options in addition to HMA and venetoclax in treating elderly patients with newly diagnosed AML.
- |||||||||| bortezomib / Generic mfg.
Journal: Discovery of Peptide Boronate Derivatives as Histone Deacetylase (HDAC) and Proteasome Dual Inhibitors for Overcoming Bortezomib Resistance of Multiple Myeloma. (Pubmed Central) - Nov 3, 2020
The most potent inhibitors, ZY-2 and ZY-13 showed excellent inhibition against proteasome and good selectivity against HDACs. In particular, ZY-2 not only exhibited good antiproliferative activities on MM cell lines RPMI-8226, U266 and KM3 (IC50 values of 6.66 nM, 4.31 nM and 10.1 nM, respectively) but also showed more potent antiproliferative activities against the bortezomib resistant MM cell line KM3/BTZ compared with bortezomib (IC50 values of 8.98 nM vs. 226 nM, P < 0.01) and even better than the combination of HDAC inhibitor MS-275 and bortezomib (1:1) (IC50 values of 8.98 nM vs. 98.0 nM, P < 0.01).
- |||||||||| Zolinza (vorinostat) / Merck (MSD), entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax Pharma
[VIRTUAL] Class specific HDAC inhibition differentially affects the function of specific T cell subsets (virtual poster hall) - Nov 3, 2020 - Abstract #SITC2020SITC_2060;
Ongoing studies are aimed at elucidating the specific HDACs responsible for regulating T cell effector functions and tumor immunogenicity when targeted. Ultimately, understanding this could help identify inhibitors with the desired specificity profile for combining with immunotherapy.
- |||||||||| Zolinza (vorinostat) / Merck (MSD), entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax Pharma
[VIRTUAL] Class specific HDAC inhibition differentially affects the function of specific T cell subsets (virtual poster hall) - Nov 3, 2020 - Abstract #SITC2020SITC_1981;
Ongoing studies are aimed at elucidating the specific HDACs responsible for regulating T cell effector functions and tumor immunogenicity when targeted. Ultimately, understanding this could help identify inhibitors with the desired specificity profile for combining with immunotherapy.
- |||||||||| entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax Pharma
Journal: Novel aroylated phenylenediamine compounds enhance antimicrobial defense and maintain airway epithelial barrier integrity. (Pubmed Central) - Oct 31, 2020
Induction was initially defined with respect to dose and time and compared with the APD Entinostat (MS-275)...The APD effects are mediated through Signal transducer and activator of transcription 3 (STAT3) activation. Utilization of induced innate immunity to fight infections can reduce antibiotic usage, might be effective against multidrug resistant bacteria and is in line with improved stewardship in healthcare.
- |||||||||| entinostat (SNDX-275) / Kyowa Hakko Kirin, Syndax
Preclinical, Journal: Regulatory mechanism of MS275 on the p38 MAPK signaling pathway in rats with convulsion in the developmental stage (Pubmed Central) - Sep 27, 2020
Trial completion date: Apr 2021 --> Sep 2020 | Trial primary completion date: Apr 2021 --> Sep 2020 In rats with convulsion in the developmental stage, the histone deacetylase inhibitor MS275 can inhibit the p38 MAPK signaling pathway, the apoptosis of hippocampal neurons, and the activation of microglial cells and thus reduce inflammatory response and convulsion-induced brain injury in a dose-dependent manner.
- |||||||||| 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: 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
- |||||||||| Niktimvo (axatilimab-csfr) / Syndax Pharma, Incyte
Enrollment closed, Trial completion date, Trial primary completion date, Monotherapy: A Phase 1 Study to Investigate Axatilimab 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: 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.
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