Browsing by Subject "Histone deacetylase inhibitors"

Now showing 1 - 3 of 3
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    E2112: Randomized Phase III Trial of Endocrine Therapy Plus Entinostat or Placebo in Hormone Receptor-Positive Advanced Breast Cancer. A Trial of the ECOG-ACRIN Cancer Research Group
    (American Society of Clinical Oncology, 2021) Connolly, Roisin M.; Zhao, Fengmin; Miller, Kathy D.; Lee, Min-Jung; Piekarz, Richard L.; Smith, Karen L.; Brown-Glaberman, Ursa A.; Winn, Jennifer S.; Faller, Bryan A.; Onitilo, Adedayo A.; Burkard, Mark E.; Budd, George T.; Levine, Ellis G.; Royce, Melanie E.; Kaufman, Peter A.; Thomas, Alexandra; Trepel, Jane B.; Wolff, Antonio C.; Sparano, Joseph A.; Medicine, School of Medicine
    Purpose: Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with the use of histone deacetylase inhibitors such as entinostat. The ENCORE301 phase II study reported improvement in progression-free survival (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Patients and methods: E2112 is a multicenter, randomized, double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease progressed after nonsteroidal AI. Participants were randomly assigned to exemestane 25 mg by mouth once daily and entinostat (EE) or placebo (EP) 5 mg by mouth once weekly. Primary end points were PFS by central review and OS. Secondary end points included safety, objective response rate, and lysine acetylation change in peripheral blood mononuclear cells between baseline and cycle 1 day 15. Results: Six hundred eight patients were randomly assigned during March 2014-October 2018. Median age was 63 years (range 29-91), 60% had visceral disease, and 84% had progressed after nonsteroidal AI in metastatic setting. Previous treatments included chemotherapy (60%), fulvestrant (30%), and cyclin-dependent kinase inhibitor (35%). Most common grade 3 and 4 adverse events in the EE arm included neutropenia (20%), hypophosphatemia (14%), anemia (8%), leukopenia (6%), fatigue (4%), diarrhea (4%), and thrombocytopenia (3%). Median PFS was 3.3 months (EE) versus 3.1 months (EP; hazard ratio = 0.87; 95% CI, 0.67 to 1.13; P = .30). Median OS was 23.4 months (EE) versus 21.7 months (EP; hazard ratio = 0.99; 95% CI, 0.82 to 1.21; P = .94). Objective response rate was 5.8% (EE) and 5.6% (EP). Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients. Conclusion: The combination of exemestane and entinostat did not improve survival in AI-resistant advanced HR-positive, HER2-negative breast cancer.
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    Epigenetic Attire in Ovarian Cancer: The Emperor’s New Clothes
    (American Association for Cancer Research, 2020-09-15) Matei, Daniela; Nephew, Kenneth P.; Anatomy and Cell Biology, School of Medicine
    Ovarian cancer is an aggressive epithelial tumor that remains a major cause of cancer morbidity and mortality in women. Epigenetic alterations including DNA methylation and histone modifications are being characterized in ovarian cancer and have been functionally linked to processes involved in tumor initiation, chemotherapy resistance, cancer stem cell survival, and tumor metastasis. The epigenetic traits of cancer cells and of associated tumor microenvironment components have been shown to promote an immunosuppressive tumor milieu. However, DNA methylation and histone modifications are reversible, and therapies targeting the epigenome have been implicated in potential reinvigoration of the antitumor immunity. In this review, we provide an overview specifically of DNA methylation and histone modifications as "clothes of the ovarian cancer genome" in relationship to their functional effects and highlight recent developments in the field. We also address the clinical implications of therapeutic strategies to remove or alter specific articles of genomic "clothing" and restore normal cellular function. As the clothes of the genome continue to be deciphered, we envision that the epigenome will become an important therapeutic target for cancer.
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    The novel histone deacetylase inhibitor, AR-42, inhibits gp130/Stat3 pathway and induces apoptosis and cell cycle arrest in multiple myeloma cells
    (Wiley, 2011-07-01) Zhang, Shuhong; Suvannasankha, Attaya; Crean, Colin D.; White, Valerie L.; Chen, Ching-Shih; Farag, Sherif S.; Department of Internal Medicine, IU School of Medicine
    Multiple myeloma (MM) remains incurable with current therapy, indicating the need for continued development of novel therapeutic agents. We evaluated the activity of a novel phenylbutyrate-derived histone deacetylase inhibitor, AR-42, in primary human myeloma cells and cell lines. AR-42 was cytotoxic to MM cells at a mean LC(50) of 0.18 ± 0.06 μmol/l at 48 hr and induced apoptosis with cleavage of caspases 8, 9 and 3, with cell death largely prevented by caspase inhibition. AR-42 downregulated the expression of gp130 and inhibited activation of STAT3, with minimal effects on the PI3K/Akt and MAPK pathways, indicating a predominant effect on the gp130/STAT-3 pathway. AR-42 also inhibited interleukin (IL)-6-induced STAT3 activation, which could not be overcome by exogenous IL-6. AR-42 also downregulated the expression of STAT3-regulated targets, including Bcl-xL and cyclin D1. Overexpression of Bcl-xL by a lentivirus construct partly protected against cell death induced by AR-42. The cyclin dependent kinase inhibitors, p16 and p21, were also significantly induced by AR-42, which together with a decrease in cyclin D1, resulted in G(1) and G(2) cell cycle arrest. In conclusion, AR-42 has potent cytotoxicity against MM cells mainly through gp130/STAT-3 pathway. The results provide rationale for clinical investigation of AR-42 in MM.