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

TitleCombined EZH2 and Bcl-2 inhibitors as precision therapy for genetically defined DLBCL subtypes.
Publication TypeJournal Article
Year of Publication2020
AuthorsScholze H, Stephenson RE, Reynolds R, Shah S, Puri R, Butler SD, Trujillo-Alonso V, Teater MR, van Besien H, Gibbs-Curtis D, Ueno H, Parvin S, Letai A, Mathew S, Singh A, Cesarman E, Melnick A, Giulino-Roth L
JournalBlood Adv
Volume4
Issue20
Pagination5226-5231
Date Published2020 10 27
ISSN2473-9537
KeywordsAntineoplastic Agents, Apoptosis, Bridged Bicyclo Compounds, Heterocyclic, Enhancer of Zeste Homolog 2 Protein, Humans, Lymphoma, Large B-Cell, Diffuse, Proto-Oncogene Proteins c-bcl-2, Sulfonamides
Abstract

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.

DOI10.1182/bloodadvances.2020002580
Alternate JournalBlood Adv
PubMed ID33104794
PubMed Central IDPMC7594393
Grant ListR01 CA238745 / CA / NCI NIH HHS / United States
R33 CA212968 / CA / NCI NIH HHS / United States
R35 CA242427 / CA / NCI NIH HHS / United States
Related Faculty: 
Ethel Cesarman, M.D., Ph.D.

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