Entinostat (MS-275,SNDX-275)

Entinostat (also known as MS-275 or SNDX-275), a derivative of 2-aminophenyl benzamides, is a potent and orally-available inhibitor of histone deacetylases (HDACs), a family of enzymes associated with a variety of well-characterized cellular oncogenes and tumor suppressors, that potently inhibits class I HDACs, including HDAC1, HDAC3 and HDAC8, with values of 50% inhibition concentration IC₅₀ of 0.368 μM, 0.501 μM and 63.4 μM respectively. Entinostat has been widely investigated for the treatment of cancer, in which results have shown the in vitro anti-proliferative activity of entinostat in a wide range of human cancer cell lines, including breast, colon, lung, myeloma, ovary, pancreas, prostate and leukemia.

Reference

Hess-Stumpp H, Bracker TU, Henderson D, Politz O. MS-275, a potent orally available inhibitor of histone deacetylases--the development of an anticancer agent. Int J Biochem Cell Biol. 2007;39(7-8):1388-405. Epub 2007 Feb 16.

Hess-Stumpp H. Histone deacetylase inhibitors and cancer: from cell biology to the clinic. Eur J Cell Biol. 2005 Mar;84(2-3):109-21.

Immunomodulation by Entinostat in Renal Cell Carcinoma Patients Receiving High-Dose Interleukin 2: A Multicenter, Single-Arm, Phase I/II Trial (NCI-CTEP#7870).[Pubmed:28939740]

Clin Cancer Res. 2017 Dec 1;23(23):7199-7208.

Purpose: On the basis of preclinical data suggesting that the class I selective HDAC inhibitor entinostat exerts a synergistic antitumor effect in combination with high-dose IL2 in a renal cell carcinoma model by downregulating Foxp3 expression and function of regulatory T cells (Treg), we conducted a phase I/II clinical study with entinostat and high-dose IL2 in patients with metastatic clear cell renal cell carcinoma (ccRCC).Experimental Design: Clear cell histology, no prior treatments, and being sufficiently fit to receive high-dose IL2 were the main eligibility criteria. The phase I portion consisted of two dose levels of entinostat (3 and 5 mg, orally every 14 days) and a fixed standard dose of IL2 (600,000 U/kg i.v.). Each cycle was 85 days. The primary endpoint was objective response rate and toxicity. Secondary endpoints included progression-free survival and overall survival.Results: Forty-seven patients were enrolled. At a median follow-up of 21.9 months, the objective response rate was 37% [95% confidence interval (CI), 22%-53%], the median progression-free survival was 13.8 months (95% CI, 6.0-18.8), and the median overall survival was 65.3 months (95% CI, 52.6.-65.3). The most common grade 3/4 toxicities were hypophosphatemia (16%), lymphopenia (15%), and hypocalcemia (7%), and all were transient. Decreased Tregs were observed following treatment with entinostat, and lower numbers were associated with response (P = 0.03).Conclusions: This trial suggests a promising clinical activity for entinostat in combination with high-dose IL2 in ccRCC patients and provides the first example of an epigenetic agent being rationally combined with immunotherapy. Clin Cancer Res; 23(23); 7199-208. (c)2017 AACR.

Effect of entinostat on NK cell-mediated cytotoxicity against osteosarcoma cells and osteosarcoma lung metastasis.[Pubmed:28919994]

Oncoimmunology. 2017 Jul 11;6(8):e1333214.

There is a crucial need for a new therapeutic approach for osteosarcoma (OS) lung metastasis since this disease remains the main cause of mortality in OS. We previously demonstrated that natural killer (NK) cell therapy has minimal efficacy against OS metastasis. This study determined whether the histone deacetylase inhibitor entinostat could immunosensitize OS cells to NK cell lysis and increases the efficacy of NK cell therapy for OS lung metastasis. Entinostat upregulated ligands for NK cell-activating receptors (major histocompatibility complex [MHC] class I polypeptide-related chain A [MICA] and B [MICB]; UL16 binding proteins 1, 2, 5, and 6; and CD155) on OS cells both in vitro and in vivo and led to more susceptibility to NK cell-mediated cytotoxicity in vitro. Importantly, entinostat did not change NK cell viability, receptor expression, or function within the 24-h treatment. We also demonstrated two potential mechanisms by which entinostat enhanced expression of MICA and MICB on OS cells. Although entinostat upregulated ligands for the NK cell activating receptor on OS lung metastasis, it failed to augment the efficacy of NK cell therapy in our nude mouse human OS lung metastasis model. This can be partly explained by our finding that although the infused NK cells were active and functional and could penetrate into the lungs, they failed to infiltrate into the lung nodules. These challenges regarding cellular immunotherapy against solid tumors may be overcome by combination therapy, such as adding a NK cell-activating cytokine (IL-2 or IL-21).

Targeting triple negative breast cancer with histone deacetylase inhibitors.[Pubmed:28952409]

Expert Opin Investig Drugs. 2017 Nov;26(11):1199-1206.

INTRODUCTION: Triple negative breast cancer (TNBC) is a heterogeneous disease characterized by poor outcomes, higher rates of relapse, lack of biomarkers for rational use of targeted treatments and insensitivity to current available treatments. Histone deacetylase inhibitors (HDACis) perform multiple cytotoxic actions and are emerging as promising multifunctional agents in TNBC. Areas covered: This review focuses on the challenges so far addressed in the targeted treatment of TNBC and explores the various mechanisms by which HDACis control cancer cell growth, tumor progression and metastases. Pivotal preclinical trials on HDACis like panobinostat, vorinostat, and entinostat show that these epigenetic agents exert an anti-proliferative effect on TNBC cells and control tumor growth by multiple mechanisms of action, including apoptosis and regulation of the epithelial to mesenchimal transition (EMT). Combination studies have reported the synergism of HDACis with other anticancer agents. Expert opinion: In recent years, treatment of TNBC has recorded a high number of failures in the development of targeted agents. HDACis alone or in combination strategies show promising activity in TNBC and could have implications for the future targeted treatment of TNBC patients. Future research should identify which agent synergizes better with HDACis and which patient will benefit more from these epigenetic agents.

Histone Deacetylases as New Therapeutic Targets in Triple-negative Breast Cancer: Progress and Promises.[Pubmed:28870998]

Cancer Genomics Proteomics. 2017 Sep-Oct;14(5):299-313.

Triple-negative breast cancer (TNBC) lacks expression of estrogen receptor (ER), progesterone receptor (PR) and HER2 gene. It comprises approximately 15-20% of breast cancers (BCs). Unfortunately, TNBC's treatment continues to be a clinical problem because of its relatively poor prognosis, its aggressiveness and the lack of targeted therapies, leaving chemotherapy as the mainstay of treatment. It is essential to find new therapies against TNBC, in order to surpass the resistance and the invasiveness of already existing therapies. Given the fact that epigenetic processes control both the initiation and progression of TNBC, there is an increasing interest in the mechanisms, molecules and signaling pathways that participate at the epigenetic modulation of genes expressed in carcinogenesis. The acetylation of histone proteins provokes the transcription of genes involved in cell growth, and the expression of histone deacetylases (HDACs) is frequently up-regulated in many malignancies. Unfortunately, in the field of BC, HDAC inhibitors have shown limited effect as single agents. Nevertheless, their use in combination with kinase inhibitors, autophagy inhibitors, ionizing radiation, or two HDAC inhibitors together is currently being evaluated. HDAC inhibitors such as suberoylanilidehydroxamic acid (SAHA), sodium butyrate, mocetinostat, panobinostat, entinostat, YCW1 and N-(2-hydroxyphenyl)-2-propylpentanamide have shown promising therapeutic outcomes against TNBC, especially when they are used in combination with other anticancer agents. More studies concerning HDAC inhibitors in breast carcinomas along with a more accurate understanding of the TNBC's pathobiology are required for the possible identification of new therapeutic strategies.

Use of a genome-wide haploid genetic screen to identify treatment predicting factors: a proof-of-principle study in pancreatic cancer.[Pubmed:28969017]

Oncotarget. 2017 Jun 29;8(38):63635-63645.

The ability to develop a comprehensive panel of treatment predicting factors would significantly improve our ability to stratify patients for cytotoxic or targeted therapies, and prevent patients receiving ineffective treatments. We have investigated if a recently developed genome-wide haploid genetic screen can be used to reveal the critical mediators of response to anticancer therapy. Pancreatic cancer is known to be highly resistant to systemic therapy. Recently epigenetic changes have been shown to be a key determinant in the maintenance of subpopulations of cancer cells with high-level resistance to cytotoxic therapy. We show that in human pancreatic cancer cell lines, treatment with the potent class I histone deacetylase inhibitor, entinostat, synergistically enhances gemcitabine-induced inhibition of cell proliferation and apoptosis. Using a genome-wide haploid genetic screen, we identified deoxycytidine kinase (DCK) as one of the genes with the highest degree of insertional enrichment following treatment with gemcitabine and entinostat; DCK is already known to be the rate-limiting activating enzyme for gemcitabine. Immunoblotting confirmed loss of DCK protein expression in the resistant KBM7 cells. CRISPR/Cas-9 inactivation of DCK in pancreatic cancer cell lines resulted in resistance to gemcitabine alone and in combination with entinostat. We have identified gemcitabine and entinostat as a potential new combination therapy in pancreatic cancer, and in this proof-of-principle study we have demonstrated that a recently developed haploid genetic screen can be used as a novel approach to identify the critical genes that determine treatment response.

Entinostat is an oral and selective class I HDAC inhibitor, with IC50s of 243 nM, 453 nM, and 248 nM for HDAC1, HDAC2, and HDAC3, respectively.

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