gsk-2816126 and Lymphoma--B-Cell

Enhancer of zeste homolog 2 (EZH2) activity is dysregulated in many cancers.. This phase I study determined the safety, maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of the intravenously administered, highly selective EZH2 inhibitor, GSK2816126, (NCT02082977). Doses of GSK2816126 ranged from 50 to 3,000 mg twice weekly, and GSK2816126 was given 3-weeks-on/1-week-off in 28-day cycles. Eligible patients had solid tumors or B-cell lymphomas with no available standard treatment regimen.. Forty-one patients (21 solid tumors, 20 lymphoma) received treatment. All patients experienced ≥1 adverse event (AE). Fatigue [22 of 41 (53.7%)] and nausea [20 of 41 (48.8%)] were the most common toxicity. Twelve (32%) patients experienced a serious AE. Dose-limiting elevated liver transaminases occurred in 2 of 7 patients receiving 3,000 mg of GSK2816126; 2,400 mg was therefore established as the MTD. Following intravenous administration of 50 to 3,000 mg twice weekly, plasma GSK2816126 levels decreased biexponentially, with a mean terminal elimination half-life of approximately 27 hours. GSK2816126 exposure (maximum observed plasma concentration and area under the plasma-time curve) increased in a dose-proportional manner. No change from baseline in H3K27me3 was seen in peripheral blood mononuclear cells. Fourteen of 41 (34%) patients had radiological best response of stable disease, 1 patient with lymphoma achieved a partial response, 21 of 41 (51%) patients had progressive disease, and 5 patients were unevaluable for antitumor response.. The MTD of GSK2816126 was established at 2,400 mg, but the dosing method and relatively short half-life limited effective exposure, and modest anticancer activity was observed at tolerable doses.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Enhancer of Zeste Homolog 2 Protein; Female; Humans; Indoles; Lymphoma, B-Cell; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Patient Safety; Prognosis; Pyridones; Tissue Distribution; Young Adult

The enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 that catalyzes methylation of histone H3 lysine 27 (H3K27). Overexpression or mutation of EZH2 has been identified in hematologic malignancies and solid tumors. Based on the structure of EPZ6438 (

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Humans; Lymphoma, B-Cell; Mice; Models, Molecular; Molecular Structure; Neoplasms, Experimental; Structure-Activity Relationship; Tumor Cells, Cultured

Loss of CD58 is a common mechanism for tumor immune evasion in lymphoid malignancies. CD58 loss is known to occur due to both genetic and non-genetic causes; therefore, we hypothesized that restoring CD58 expression in lymphoma cells may be an effective treatment approach. To explore the potential for restoring CD58 expression, we first screened 11 B-cell lymphoma lines and found that 3 had decreased CD58 expression. Among these, CD58 was genetically damaged in two lines but not in the third line. Using the cell line with downregulated CD58 without a genetic abnormality, we performed epigenetic library screening and found that two EZH2 inhibitors, EPZ6438 and GSK126, specifically enhanced CD58 expression. By examining the effect of three EZH2 inhibitors with different selectivity profiles in different B-cell lines, EZH2 inhibition was shown to have a common activity in upregulating CD58 expression. Restoring the expression of CD58 in lymphoma cells using an EZH2 inhibitor was shown to enhance interferon-γ production of T and NK cells against lymphoma cells. H3K27 was shown to be highly trimethylated in the CD58 promoter region, and EZH2 inhibition induced its demethylation and activated transcription of the CD58 gene. These results indicated that EZH2 is involved in the epigenetic silencing of CD58 in lymphoma cells as a mechanism for tumor immune escape, and EZH2 inhibitors are able to restore epigenetically suppressed CD58 expression. Our findings provide a molecular basis for the combination of an EZH2 inhibitor and immunotherapy for lymphoma treatment.

Topics: Antineoplastic Agents; Benzamides; Biphenyl Compounds; CD58 Antigens; Cell Line, Tumor; Enhancer of Zeste Homolog 2 Protein; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Gene Silencing; Humans; Indoles; Lymphocyte Activation; Lymphoma, B-Cell; Morpholines; Pyridones; T-Lymphocytes