Development of venetoclax for therapy of lymphoid malignancies

Huayuan Zhu,1,2 Alexandru Almasan1 1Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; 2Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, People’s Republic of China Abstra...

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Main Authors: Zhu H, Almasan A
Format: Article
Language:English
Published: Dove Medical Press 2017-03-01
Series:Drug Design, Development and Therapy
Subjects:
Online Access:https://www.dovepress.com/development-of-venetoclax-for-therapy-of-lymphoid-malignancies-peer-reviewed-article-DDDT
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spelling doaj-da53006b5f97497785664f195bfb65652020-11-24T20:41:28ZengDove Medical PressDrug Design, Development and Therapy1177-88812017-03-01Volume1168569431772Development of venetoclax for therapy of lymphoid malignanciesZhu HAlmasan AHuayuan Zhu,1,2 Alexandru Almasan1 1Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; 2Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, People’s Republic of China Abstract: B-cell lymphoma-2 (BCL-2) family dysfunction and impairment of apoptosis are common in most B-cell lymphoid malignancies. Venetoclax (Venclexta™, formerly ABT-199, GDC-0199) is a highly selective BCL-2 inhibitor, which mimics its BCL-2 homology 3-domain to induce apoptosis. It was approved for treatment of previously treated chronic lymphocytic leukemia (CLL) patients with 17p deletion early in 2016. It has also been in clinical trials for other B-cell lymphoid malignancies. Unlike the other recently approved targeted agents idelalisib and ibrutinib, so far there has been no relapse reported in some patients. Also, unlike the other targeted agents, it is effective against tumor cells that reside in the blood marrow. Despite its promising outcome in CLL, preclinical data have already uncovered mechanistic insights underlying venetoclax resistance, such as upregulation of MCL-1 or BCL-xL expression and protective signaling from the microenvironment. In this review, we describe the role of the BCL-2 family in the pathogenesis of B-cell lymphoid malignancies, the development of venetoclax, and its current clinical outcome in CLL and other B-cell malignancies. We also discuss the resistance mechanisms that develop following venetoclax therapy, potential strategies to overcome them, and how this knowledge can be translated into clinical applications. Keywords: BCL-2, BCL-xL, chronic lymphocytic leukemia, MCL-1, venetoclaxhttps://www.dovepress.com/development-of-venetoclax-for-therapy-of-lymphoid-malignancies-peer-reviewed-article-DDDTBcl-2Bcl-xLchronic lymphocytic leukemiaMcl-1venetoclax
collection DOAJ
language English
format Article
sources DOAJ
author Zhu H
Almasan A
spellingShingle Zhu H
Almasan A
Development of venetoclax for therapy of lymphoid malignancies
Drug Design, Development and Therapy
Bcl-2
Bcl-xL
chronic lymphocytic leukemia
Mcl-1
venetoclax
author_facet Zhu H
Almasan A
author_sort Zhu H
title Development of venetoclax for therapy of lymphoid malignancies
title_short Development of venetoclax for therapy of lymphoid malignancies
title_full Development of venetoclax for therapy of lymphoid malignancies
title_fullStr Development of venetoclax for therapy of lymphoid malignancies
title_full_unstemmed Development of venetoclax for therapy of lymphoid malignancies
title_sort development of venetoclax for therapy of lymphoid malignancies
publisher Dove Medical Press
series Drug Design, Development and Therapy
issn 1177-8881
publishDate 2017-03-01
description Huayuan Zhu,1,2 Alexandru Almasan1 1Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; 2Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, People’s Republic of China Abstract: B-cell lymphoma-2 (BCL-2) family dysfunction and impairment of apoptosis are common in most B-cell lymphoid malignancies. Venetoclax (Venclexta™, formerly ABT-199, GDC-0199) is a highly selective BCL-2 inhibitor, which mimics its BCL-2 homology 3-domain to induce apoptosis. It was approved for treatment of previously treated chronic lymphocytic leukemia (CLL) patients with 17p deletion early in 2016. It has also been in clinical trials for other B-cell lymphoid malignancies. Unlike the other recently approved targeted agents idelalisib and ibrutinib, so far there has been no relapse reported in some patients. Also, unlike the other targeted agents, it is effective against tumor cells that reside in the blood marrow. Despite its promising outcome in CLL, preclinical data have already uncovered mechanistic insights underlying venetoclax resistance, such as upregulation of MCL-1 or BCL-xL expression and protective signaling from the microenvironment. In this review, we describe the role of the BCL-2 family in the pathogenesis of B-cell lymphoid malignancies, the development of venetoclax, and its current clinical outcome in CLL and other B-cell malignancies. We also discuss the resistance mechanisms that develop following venetoclax therapy, potential strategies to overcome them, and how this knowledge can be translated into clinical applications. Keywords: BCL-2, BCL-xL, chronic lymphocytic leukemia, MCL-1, venetoclax
topic Bcl-2
Bcl-xL
chronic lymphocytic leukemia
Mcl-1
venetoclax
url https://www.dovepress.com/development-of-venetoclax-for-therapy-of-lymphoid-malignancies-peer-reviewed-article-DDDT
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