Combined EZH2 and Bcl-2 inhibitors as precision therapy for genetically defined DLBCL subtypes.

Autor:	Scholze H; Department of Pediatrics, Weill Cornell Medical College, New York, NY., Stephenson RE; Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY., Reynolds R; Department of Pathology and Laboratory Medicine and., Shah S; Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY., Puri R; Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY., Butler SD; Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY., Trujillo-Alonso V; Department of Pediatrics, Weill Cornell Medical College, New York, NY., Teater MR; Department of Medicine, Weill Cornell Medical College, New York, NY., van Besien H; Department of Pathology and Laboratory Medicine and., Gibbs-Curtis D; Department of Pathology and Laboratory Medicine and., Ueno H; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY., Parvin S; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., Letai A; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., Mathew S; Department of Pathology and Laboratory Medicine and., Singh A; Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA; and.; Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta GA., Cesarman E; Department of Pathology and Laboratory Medicine and., Melnick A; Department of Medicine, Weill Cornell Medical College, New York, NY., Giulino-Roth L; Department of Pediatrics, Weill Cornell Medical College, New York, NY.; Department of Pathology and Laboratory Medicine and.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2020 Oct 27; Vol. 4 (20), pp. 5226-5231.
DOI:	10.1182/bloodadvances.2020002580
Abstrakt:	Molecular alterations in the histone methyltransferase EZH2 and the antiapoptotic protein Bcl-2 frequently co-occur in diffuse large B-cell lymphoma (DLBCL). Because DLBCL tumors with these characteristics are likely dependent on both oncogenes, dual targeting of EZH2 and Bcl-2 is a rational therapeutic approach. We hypothesized that EZH2 and Bcl-2 inhibition would be synergistic in DLBCL. To test this, we evaluated the EZH2 inhibitor tazemetostat and the Bcl-2 inhibitor venetoclax in DLBCL cells, 3-dimensional lymphoma organoids, and patient-derived xenografts (PDXs). We found that tazemetostat and venetoclax are synergistic in DLBCL cells and 3-dimensional lymphoma organoids that harbor an EZH2 mutation and an IGH/BCL2 translocation but not in wild-type cells. Tazemetostat treatment results in upregulation of proapoptotic Bcl-2 family members and priming of mitochondria to BH3-mediated apoptosis, which may sensitize cells to venetoclax. The combination of tazemetostat and venetoclax was also synergistic in vivo. In DLBCL PDXs, short-course combination therapy resulted in complete remissions that were durable over time and associated with superior overall survival compared with either drug alone. (© 2020 by The American Society of Hematology.)
Databáze:	MEDLINE
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