Venetoclax Synergizes with Radiotherapy for Treatment of B-cell Lymphomas.

Autor:	O'Steen S; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. sosteen@fredhutch.org., Green DJ; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Department of Medicine, University of Washington, Seattle, Washington., Gopal AK; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Department of Medicine, University of Washington, Seattle, Washington., Orozco JJ; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Department of Medicine, University of Washington, Seattle, Washington., Kenoyer AL; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Lin Y; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Wilbur DS; Department of Radiation Oncology, University of Washington, Seattle, Washington., Hamlin DK; Department of Radiation Oncology, University of Washington, Seattle, Washington., Fisher DR; Versant Physics, Richland, Washington., Hylarides MD; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Gooley TA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Waltman A; University of Chicago, Chicago, Illinois., Till BG; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Department of Medicine, University of Washington, Seattle, Washington., Press OW; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Department of Medicine, University of Washington, Seattle, Washington.; Department of Bioengineering, University of Washington, Seattle, Washington.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2017 Jul 15; Vol. 77 (14), pp. 3885-3893. Date of Electronic Publication: 2017 May 31.
DOI:	10.1158/0008-5472.CAN-17-0082
Abstrakt:	Constitutive B-cell receptor signaling leads to overexpression of the antiapoptotic BCL-2 protein and is implicated in the pathogenesis of many types of B-cell non-Hodgkin lymphoma (B-NHL). The BCL-2 small-molecule inhibitor venetoclax shows promising clinical response rates in several lymphomas, but is not curative as monotherapy. Radiotherapy is a rational candidate for combining with BCL-2 inhibition, as DNA damage caused by radiotherapy increases the activity of pro-apoptotic BCL-2 pathway proteins, and lymphomas are exquisitely sensitive to radiation. We tested B-NHL responses to venetoclax combined with either external beam radiotherapy or radioimmunotherapy (RIT), which joins the selectivity of antibody targeting with the effectiveness of irradiation. We first tested cytotoxicity of cesium-137 irradiation plus venetoclax in 14 B-NHL cell lines representing five lymphoma subtypes. Combination treatment synergistically increased cell death in 10 of 14 lines. Lack of synergy was predicted by resistance to single-agent venetoclax and high BCL-XL expression. We then assessed the efficacy of external beam radiotherapy plus venetoclax in murine xenograft models of mantle cell (MCL), germinal-center diffuse large B-cell (GCB-DLBCL), and activated B-cell (ABC-DLBCL) lymphomas. In each model, external beam radiotherapy plus venetoclax synergistically increased mouse survival time, curing up to 10%. We finally combined venetoclax treatment of MCL and ABC-DLBCL xenografts with a pretargeted RIT (PRIT) system directed against the CD20 antigen. Optimal dosing of PRIT plus venetoclax cured 100% of mice with no detectable toxicity. Venetoclax combined with radiotherapy may be a promising treatment for a wide range of lymphomas Cancer Res; 77(14); 3885-93. ©2017 AACR . (©2017 American Association for Cancer Research.)
Databáze:	MEDLINE
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