Entinostat: a promising treatment option for patients with advanced breast cancer

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

• 1 NIH. Cancer Stat Facts: Female Breast Cancer. http://seer.cancer.gov/statfacts/html/breast.html.
  Google Scholar
• 2 Baselga J, Campone M, Piccart M et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366(6), 520–529 (2012).
  Medline CASGoogle Scholar
• 3 Finn RS, Crown JP, Lang I et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised Phase II study. Lancet Oncol. 16(1), 25–35 (2015).
  Medline CASGoogle Scholar
• 4 Cristofanilli M, Turner NC, Bondarenko I et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, Phase III randomised controlled trial. Lancet Oncol. 17(4), 425–439 (2016).
  Medline CASGoogle Scholar
• 5 Baylin SB, Jones PA. A decade of exploring the cancer epigenome – biological and translational implications. Nat. Rev. Cancer 11(10), 726–734 (2011).
  Medline CASGoogle Scholar
• 6 Krusche CA, Wulfing P, Kersting C et al. Histone deacetylase-1 and -3 protein expression in human breast cancer: a tissue microarray analysis. Breast Cancer Res. Treat. 90(1), 15–23 (2005).
  Medline CASGoogle Scholar
• 7 Muller BM, Jana L, Kasajima A et al. Differential expression of histone deacetylases HDAC1, 2 and 3 in human breast cancer-overexpression of HDAC2 and HDAC3 is associated with clinicopathological indicators of disease progression. BMC Cancer 13, 215 (2013).
  Medline CASGoogle Scholar
• 8 Connolly R, Stearns V. Epigenetics as a therapeutic target in breast cancer. J. Mammary Gland Biol. Neoplasia 17(3–4), 191–204 (2012).
  MedlineGoogle Scholar
• 9 Amir E, Seruga B, Niraula S, Carlsson L, Ocana A. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J. Natl Cancer Inst. 103(17), 1299–1309 (2011).
  Medline CASGoogle Scholar
• 10 Robertson JF, Llombart-Cussac A, Rolski J et al. Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the FIRST study. J. Clin. Oncol. 27(27), 4530–4535 (2009).
  Medline CASGoogle Scholar
• 11 Mohla S, Stearns V, Sathyamoorthy N, Rosenfeld MG, Nelson P. The biology of hormone refractory breast and prostate cancer: an NCI workshop report. Cancer Biol. Ther. 8(21), 1975–1985 (2009).
  Medline CASGoogle Scholar
• 12 Finn RS, Crown JP, Lang I et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised Phase 2 study. Lancet 16(1), 25–35 (2015).
  Medline CASGoogle Scholar
• 13 Finn RS, Martin M, Rugo HS et al. Palbociclib and letrozole in advanced breast cancer. N. Engl. J. Med. 375(20), 1925–1936 (2016).
  Medline CASGoogle Scholar
• 14 Yardley DA, Ismail-Khan RR, Melichar B et al. Randomized Phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. J. Clin. Oncol. 31(17), 2128–2135 (2013). •• Phase II clinical trial in patients with advanced hormone receptor-positive breast cancer which indicated a survival advantage for the combination of exemestane and entinostat versus exemestane and placebo.
  Medline CASGoogle Scholar
• 15 Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat. Rev. Genet. 3(6), 415–428 (2002).
  Medline CASGoogle Scholar
• 16 Arts J, De Schepper S, Van Emelen K. Histone deacetylase inhibitors: from chromatin remodeling to experimental cancer therapeutics. Curr. Med. Chem. 10(22), 2343–2350 (2003).
  Medline CASGoogle Scholar
• 17 Prince HM, Bishton MJ, Harrison SJ. Clinical studies of histone deacetylase inhibitors. Clin. Cancer. Res. 15(12), 3958–3969 (2009).
  Medline CASGoogle Scholar
• 18 Saito A, Yamashita T, Mariko Y et al. A synthetic inhibitor of histone deacetylase, MS-27–275, with marked in vivo antitumor activity against human tumors. Proc. Natl Acad. Sci. USA 96(8), 4592–4597 (1999). • Early preclinical study highlighting the antitumor activity in vivo of entinostat against human tumors.
  Medline CASGoogle Scholar
• 19 Suzuki T, Ando T, Tsuchiya K et al. Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives. J. Med. Chem. 42(15), 3001–3003 (1999).
  Medline CASGoogle Scholar
• 20 Buglio D, Khaskhely NM, Voo KS, Martinez-Valdez H, Liu YJ, Younes A. HDAC11 plays an essential role in regulating OX40 ligand expression in Hodgkin lymphoma. Blood 117(10), 2910–2917 (2011).
  Medline CASGoogle Scholar
• 21 Xu WS, Parmigiani RB, Marks PA. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26(37), 5541–5552 (2007).
  Medline CASGoogle Scholar
• 22 Acharya MR, Karp JE, Sausville EA et al. Factors affecting the pharmacokinetic profile of MS-275, a novel histone deacetylase inhibitor, in patients with cancer. Invest. New Drugs 24(5), 367–375 (2006).
  Medline CASGoogle Scholar
• 23 Ryan QC, Headlee D, Acharya M et al. Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. J. Clin. Oncol. 23(17), 3912–3922 (2005). • First published Phase I clinical trial of entinostat in patients with advanced malignancies, which provided information regarding pharmacokinetics and dosing information to guide future studies.
  Medline CASGoogle Scholar
• 24 Kummar S, Gutierrez M, Gardner ER et al. Phase I trial of MS-275, a histone deacetylase inhibitor, administered weekly in refractory solid tumors and lymphoid malignancies. Clin. Cancer. Res. 13(18 Pt 1), 5411–5417 (2007).
  Medline CASGoogle Scholar
• 25 Gojo I, Jiemjit A, Trepel JB et al. Phase I and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. Blood 109(7), 2781–2790 (2007).
  Medline CASGoogle Scholar
• 26 Knipstein J, Gore L. Entinostat for treatment of solid tumors and hematologic malignancies. Expert Opin. Invest. Drugs 20(10), 1455–1467 (2011).
  Medline CASGoogle Scholar
• 27 Acharya MR, Sparreboom A, Sausville EA et al. Interspecies differences in plasma protein binding of MS-275, a novel histone deacetylase inhibitor. Cancer Chemother. Pharmacol. 57(3), 275–281 (2006).
  Medline CASGoogle Scholar
• 28 Ordentlich P. Pharmacodynamic analysis of ENCORE 301, a placebo-controlled, randomized Phase II study of exemestane with and without entinostat in postmenopausal ER+ breast cancer patients demonstrates an association of lysine hyperacetylation with clinical outcome. Presented at: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. San Francisco, CA, USA, 12–16 November 2011 (Abstract PR-6).
  Google Scholar
• 29 Simonini MV, Camargo LM, Dong E et al. The benzamide MS-275 is a potent, long-lasting brain region-selective inhibitor of histone deacetylases. Proc. Natl Acad. Sci. USA 103(5), 1587–1592 (2006).
  Medline CASGoogle Scholar
• 30 Hooker JM, Kim SW, Alexoff D et al. Histone deacetylase inhibitor, MS-275, exhibits poor brain penetration: PK studies of [C]MS-275 using positron emission tomography. ACS Chem. Neurosci. 1(1), 65–73 (2010).
  Medline CASGoogle Scholar
• 31 Gore L, Rothenberg ML, O'bryant CL et al. A Phase I and pharmacokinetic study of the oral histone deacetylase inhibitor, MS-275, in patients with refractory solid tumors and lymphomas. Clin. Cancer. Res. 14(14), 4517–4525 (2008).
  Medline CASGoogle Scholar
• 32 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. 39(7–8), 1388–1405 (2007).
  Medline CASGoogle Scholar
• 33 Witta SE, Gemmill RM, Hirsch FR et al. Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res. 66(2), 944–950 (2006).
  Medline CASGoogle Scholar
• 34 Sabnis GJ, Goloubeva OG, Kazi AA, Shah P, Brodie AH. HDAC inhibitor entinostat restores responsiveness of letrozole-resistant MCF-7Ca xenografts to aromatase inhibitors through modulation of Her-2. Mol. Cancer Ther. 12(12), 2804–2816 (2013). •• Preclinical study highlighting the potential for entinostat to overcome resistance to endocrine therapy in letrozole-resistant breast cancer mouse models, which provided rationale for the Phase II ENCORE301 trial.
  Medline CASGoogle Scholar
• 35 Buglio D, Georgakis GV, Hanabuchi S et al. Vorinostat inhibits STAT6-mediated TH2 cytokine and TARC production and induces cell death in Hodgkin lymphoma cell lines. Blood 112(4), 1424–1433 (2008).
  Medline CASGoogle Scholar
• 36 Reddy P, Maeda Y, Hotary K et al. Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect. Proc. Natl Acad. Sci. USA 101(11), 3921–3926 (2004).
  Medline CASGoogle Scholar
• 37 Brogdon JL, Xu Y, Szabo SJ et al. Histone deacetylase activities are required for innate immune cell control of Th1 but not Th2 effector cell function. Blood 109(3), 1123–1130 (2007).
  Medline CASGoogle Scholar
• 38 Magner WJ, Kazim AL, Stewart C et al. Activation of MHC class I, II, and CD40 gene expression by histone deacetylase inhibitors. J. Immunol. 165(12), 7017–7024 (2000).
  Medline CASGoogle Scholar
• 39 Maeda T, Towatari M, Kosugi H, Saito H. Up-regulation of costimulatory/adhesion molecules by histone deacetylase inhibitors in acute myeloid leukemia cells. Blood 96(12), 3847–3856 (2000).
  Medline CASGoogle Scholar
• 40 Tao R, De Zoeten EF, Ozkaynak E et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat. Med. 13(11), 1299–1307 (2007).
  Medline CASGoogle Scholar
• 41 Shen L, Ciesielski M, Ramakrishnan S et al. Class I histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models. PLoS ONE 7(1), e30815 (2012). • Preclinical study investigating the immunomodulatory role of entinostat in human tumors and potential for combination of entinostat and immunotherapy to have enhanced antitumor activity.
  Medline CASGoogle Scholar
• 42 Zhou Q, Shaw PG, Davidson NE. Inhibition of histone deacetylase suppresses EGF signaling pathways by destabilizing EGFR mRNA in ER-negative human breast cancer cells. Breast Cancer Res. Treat. 117(2), 443–451 (2009).
  Medline CASGoogle Scholar
• 43 Sharma D, Saxena NK, Davidson NE, Vertino PM. Restoration of tamoxifen sensitivity in estrogen receptor-negative breast cancer cells: tamoxifen-bound reactivated ER recruits distinctive corepressor complexes. Cancer Res. 66(12), 6370–6378 (2006).
  Medline CASGoogle Scholar
• 44 Sabnis GJ, Goloubeva O, Chumsri S, Nguyen N, Sukumar S, Brodie AM. Functional activation of the estrogen receptor-alpha and aromatase by the HDAC inhibitor entinostat sensitizes ER-negative tumors to letrozole. Cancer Res. 71(5), 1893–1903 (2011).
  Medline CASGoogle Scholar
• 45 Yang X, Phillips DL, Ferguson AT, Nelson WG, Herman JG, Davidson NE. Synergistic activation of functional estrogen receptor (ER)-alpha by DNA methyltransferase and histone deacetylase inhibition in human ER-alpha-negative breast cancer cells. Cancer Res. 61(19), 7025–7029 (2001).
  Medline CASGoogle Scholar
• 46 Keen JC, Yan L, Mack KM et al. A novel histone deacetylase inhibitor, scriptaid, enhances expression of functional estrogen receptor alpha (ER) in ER negative human breast cancer cells in combination with 5-aza 2′-deoxycytidine. Breast Cancer Res. Treat. 81(3), 177–186 (2003).
  Medline CASGoogle Scholar
• 47 Fan J, Yin WJ, Lu JS et al. ER alpha negative breast cancer cells restore response to endocrine therapy by combination treatment with both HDAC inhibitor and DNMT inhibitor. J. Cancer Res. Clin. Oncol. 134(8), 883–890 (2008).
  Medline CASGoogle Scholar
• 48 Lee J, Bartholomeusz C, Mansour O et al. A class I histone deacetylase inhibitor, entinostat, enhances lapatinib efficacy in HER2-overexpressing breast cancer cells through FOXO3-mediated Bim1 expression. Breast Cancer Res. Treat. 146(2), 259–272 (2014).
  Medline CASGoogle Scholar
• 49 Connolly R, Li H, Jankowitz RC et al. Combination epigenetic therapy in advanced breast cancer with 5-azacitidine and entinostat: a Phase II National Cancer Institute/Stand Up to Cancer Study. Clin. Cancer Res. doi:10.1158/1078-0432.CCR-16-1729 (2016) (Epub ahead of print). • Phase II clinical trial in patients with advanced breast cancer which reports that administration of combination epigenetic therapy is safe and tolerable.
  Google Scholar
• 50 Kim K, Skora AD, Li Z et al. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc. Natl Acad. Sci. USA 111(32), 11774–11779 (2014).
  Medline CASGoogle Scholar
• 51 Shah P, Gau Y, Sabnis G. Histone deacetylase inhibitor entinostat reverses epithelial to mesenchymal transition of breast cancer cells by reversing the repression of E-cadherin. Breast Cancer Res. Treat. 143(1), 99–111 (2014).
  Medline CASGoogle Scholar
• 52 Park IH, Kang JH, Shin JM, Lee HM. Trichostatin A inhibits epithelial mesenchymal transition induced by TGF-beta1 in airway epithelium. PLoS ONE 11(8), e0162058 (2016).
  MedlineGoogle Scholar
• 53 Ruscetti M, Dadashian EL, Guo W et al. HDAC inhibition impedes epithelial-mesenchymal plasticity and suppresses metastatic, castration-resistant prostate cancer. Oncogene 35(29), 3781–3795 (2016).
  Medline CASGoogle Scholar
• 54 Schech A, Kazi A, Yu S, Shah P, Sabnis G. Histone deacetylase inhibitor entinostat inhibits tumor-initiating cells in triple-negative breast cancer cells. Mol. Cancer Ther. 14(8), 1848–1857 (2015).
  Medline CASGoogle Scholar
• 55 Zhu WG, Lakshmanan RR, Beal MD, Otterson GA. DNA methyltransferase inhibition enhances apoptosis induced by histone deacetylase inhibitors. Cancer Res. 61(4), 1327–1333 (2001).
  Medline CASGoogle Scholar
• 56 Belinsky SA, Klinge DM, Stidley CA et al. Inhibition of DNA methylation and histone deacetylation prevents murine lung cancer. Cancer Res. 63(21), 7089–7093 (2003).
  Medline CASGoogle Scholar
• 57 Fandy TE, Herman JG, Kerns P et al. Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies. Blood 114(13), 2764–2773 (2009).
  Medline CASGoogle Scholar
• 58 Prebet T, Sun Z, Figueroa ME et al. Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup trial E1905. J. Clin. Oncol. 32(12), 1242–1248 (2014).
  Medline CASGoogle Scholar
• 59 Juergens RA, Wrangle J, Vendetti FP et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 1(7), 598–607 (2011).
  Medline CASGoogle Scholar
• 60 Vendetti FP, Topper M, Huang P et al. Evaluation of azacitidine and entinostat as sensitization agents to cytotoxic chemotherapy in preclinical models of non-small cell lung cancer. Oncotarget 6(1), 56–70 (2015).
  MedlineGoogle Scholar
• 61 Investigator Brochure: Entinostat, SNDX-27 (2014).
  Google Scholar
• 62 Piekarz RL, Sackett DL, Bates SE. Histone deacetylase inhibitors and demethylating agents: clinical development of histone deacetylase inhibitors for cancer therapy. Cancer J. 13(1), 30–39 (2007).
  Medline CASGoogle Scholar
• 63 Munster PN, Marchion D, Thomas S et al. Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker. Br. J. Cancer 101(7), 1044–1050 (2009).
  Medline CASGoogle Scholar
• 64 Hodges-Gallagher L, Valentine CD, Bader SE, Kushner PJ. Inhibition of histone deacetylase enhances the anti-proliferative action of antiestrogens on breast cancer cells and blocks tamoxifen-induced proliferation of uterine cells. Breast Cancer Res. Treat. 105(3), 297–309 (2007).
  Medline CASGoogle Scholar
• 65 Munster PN, Thurn KT, Thomas S et al. A Phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer. Br. J. Cancer 104(12), 1828–1835 (2011).
  Medline CASGoogle Scholar
• 66 Tomita Y, Lee MJ, Lee S et al. The interplay of epigenetic therapy and immunity in locally recurrent or metastatic estrogen receptor-positive breast cancer: Correlative analysis of ENCORE 301, a randomized, placebo-controlled Phase II trial of exemestane with or without entinostat. Oncoimmunology 5(11), e1219008 (2016).
  MedlineGoogle Scholar
• 67 Angelika Ihle M, Merkelbach-Bruse S, Hartmann W et al. HR23b expression is a potential predictive biomarker for HDAC inhibitor treatment in mesenchymal tumours and is associated with response to vorinostat. J. Pathol. Clin. Res. 2(2), 59–71 (2016).
  MedlineGoogle Scholar
• 68 Khan O, Fotheringham S, Wood V et al. HR23B is a biomarker for tumor sensitivity to HDAC inhibitor-based therapy. Proc. Natl Acad. Sci. USA 107(14), 6532–6537 (2010).
  Medline CASGoogle Scholar
• 69 Fotheringham S, Epping MT, Stimson L et al. Genome-wide loss-of-function screen reveals an important role for the proteasome in HDAC inhibitor-induced apoptosis. Cancer Cell 15(1), 57–66 (2009).
  Medline CASGoogle Scholar