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Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Sujatha Puttalingaiah, Murthy V. Greeshma, Mahadevaswamy G. Kuruburu, Venugopal R. Bovilla, SubbaRao V. Madhunapantula
Modulation of CD8 T-cell responses with HDAC inhibitors is another important aspect in controlling tumor growth. Tumor-oriented cytolytic CD8 effector T cells, which produce IFN-γ and TNF-α, cytokines that activate APCs can make the tumor cells more immunogenic by enhancing MHC expression, activating the immunoproteasome and promoting tumor cytotoxicity (de Charette et al., 2016; Jorgovanovic et al., 2020). For example, a combination of entinostat and IL-2 elicits dramatic increases in IFN-γ production and CD8 T-cell cytotoxicity in a mouse model of renal cancer (Shen et al., 2012).
Breast cancer epigenetic targets for precision medicine
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
In a recent study, it was found that the combination of entinostat, ATRA, and doxorubicin (EAD) restored the epigenetically silenced RAR-β expression and resulted in significant tumor regression. The findings in this study suggest that Entinostat mediates Doxorubicin's action on cytotoxicity and differentiation driven by retinoids in order to achieve tumor regression in TNBC (Merino et al., 2016).
Epigenetic priming of both tumor and NK cells augments antibody-dependent cellular cytotoxicity elicited by the anti-PD-L1 antibody avelumab against multiple carcinoma cell types
Published in OncoImmunology, 2018
Kristin C. Hicks, Massimo Fantini, Renee N. Donahue, Angie Schwab, Karin M. Knudson, Sarah R. Tritsch, Caroline Jochems, Paul E. Clavijo, Clint T. Allen, James W. Hodge, Kwong Y. Tsang, Jeffrey Schlom, Sofia R. Gameiro
Data from our laboratory have previously shown that clinically relevant exposure of breast and prostate carcinoma cells to HDAC inhibitors increases their expression of human leukocyte antigen (HLA) and antigen processing and presentation proteins, reversing tumor resistance to T cell‒mediated lysis.40 Here, we used two distinct classes of HDAC inhibitors, vorinostat and entinostat, to examine the potential of epigenetic priming of multiple human carcinoma cell types and NK cell effectors to modulate the expression of NK ligands and receptors, and PD-L1. Vorinostat, a pan-HDAC inhibitor that suppresses the activity of class I and IIb HDACs, is currently approved by the Food and Drug Administration for the treatment of cutaneous T-cell lymphoma.41,42 Entinostat is a class I HDAC inhibitor under clinical investigation for the treatment of multiple malignancies.42 We also investigated the effect of entinostat on NK effector function and carcinoma sensitivity to lysis in the presence or absence of the PD-L1 targeting mAb avelumab. To the best of our knowledge, our data demonstrate for the first time that HDAC inhibition of NK and/or tumor cells enhanced avelumab-mediated ADCC. Of note, entinostat treatment promoted a more active phenotype on NK cells from healthy donor and heavily pretreated cancer patient PBMCs. Data presented here offer a rationale for combining HDAC inhibitors with mAbs targeting the PD-1/PD-L1 axis, including for patients who are refractory or expected to not respond to these therapies alone due to absent or low PD-L1 tumor expression.
What therapies are on the horizon for HER2 positive breast cancer?
Published in Expert Review of Anticancer Therapy, 2019
Giulia Viale, Stefania Morganti, Emanuela Ferraro, Paola Zagami, Antonio Marra, Giuseppe Curigliano
HDACs are enzymes that take part in the regulation of gene expression; their inhibition negatively interferes with cellular proliferation, making HDCAs a promising therapeutic target [87]. Entinostat is a HDAC 1/3 inhibitor that showed activity in preclinical studies in combination with trastuzumab or lapatinib in HER2+ MBC models. Initial results were also confirmed in a phase I clinical trial with entinostat and lapatinib ± trastuzumab with a CBR of 20% in 35 heavily pretreated patients [88].
Emerging data on improving response to hormone therapy: the role of novel targeted agents
Published in Expert Review of Anticancer Therapy, 2018
One study demonstrated that treating breast cancer cells with entinostat increased expression of the ER-alpha and aromatase as well as increased the activity of aromatase, resulting in increased sensitivity to treatment with estrogen and letrozole [102]. Breast cancer cells treated with entinostat either alone or in combination with letrozole demonstrated a decreased tumor growth rate.