Targeting of BCL2 Family Proteins with ABT-199 and Homoharringtonine Reveals BCL2- and MCL1-Dependent Subgroups of Diffuse Large B-Cell Lymphoma

Klánová, Magdalena; Anděra, Ladislav; Bražina, Jan; Švadlenka, Jan; Benesova, Simona; Soukup, J.; Průková, Dana; Vejmelkova, Dana; Jakša, Radek; Helman, Karel; Vočková, Petra; Latečková, Lucie; Molinský, Jan; Maswabi, Bokang Calvin Lenyeletse; Alam, Mohammad Zahangir; Kodet, Roman; Pytlik, Robert; Trněný, Marek; Klener, Pavel

doi:10.1158/1078-0432.ccr-15-1191

Cited by 80 publications

(96 citation statements)

References 24 publications

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“…Targeted inhibition of BCL2 with its highly selective inhibitor ABT-199 recently emerged as a promising treatment strategy for some B-cell malignancies such as CLL and MCL (26,27). ABT-199 was proved potentially effective in BCL2 positive DLBCL (28). In GCB-DLBCL with BCL2 positive might benefit from ABT-199 or other inhibitors of BCL2 function.…”

Section: Discussionmentioning

confidence: 99%

BCL2/Ki-67 index predict survival in germinal center B-cell-like diffuse large B-cell lymphoma

Tang

Zhou

Cheng³

et al. 2017

Oncology Letters

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Abstract. Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. BCL2 apoptosis regulator (BCL2) and marker of proliferation are established prognostic markers, which have traditionally been assessed separately in DLBCL. However, no studies have evaluated the prognostic value of the combination of BCL2 and Ki-67 index. Thus, the present study aimed to analyze the prognostic value of combination of these two markers. Immunohistochemical analysis was used to assess the expression of BCL2 and Ki-67 in 274 cases of DLBCL. The BCL2/Ki-67 index demonstrated a significant association with decreased overall and progression free survival of patients with DLBCL, particularly for the germinal center B-cell-like subtype of DLBCL. Following multivariate analysis, the BCL2/Ki-67 index retained prognostic significance. Patients with coexpression of BCL2 and Ki-67 constituted a unique group with poor survival, thus novel therapies targeting BCL2 protein and high proliferative activity may improve the outcome of these patients. IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), accounting for 30-40% of all NHL patients (1-3), which is considered to be a heterogeneous entity based on its biological characteristics and clinical outcomes (3-5). The survivals of DLBCL patients have notably improved since addition of rituximab to CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy (6,7). However, some DLBCL patients continue to present an inferior prognosis under standard R-CHOP therapy (1).Ki-67, a nuclear nonhistone protein, is synthesized at the beginning of cell proliferation (8). Ki-67 expression has been widely used in clinical practice as an index to evaluate the proliferative activity of lymphoma. High Ki-67 expression was highly associated with worse OS for NHL (9). However, the relationship between Ki-67 expression and outcome with DLBCL are still contradictory and inconclusive in various studies (10-12).BCL2 protein functions as an antiapoptotic protein inhibiting cells from programmed cell death (13). Both gene amplification and translocation are common mechanisms causing BCL2 protein overexpression in DLBCL. The clinical significance of BCL2 protein expression in DLBCL is still controversial. The impact of BCL2 overexpression on survival in DLBCL is still debatable in previous studies. Additionally, the prognostic value of BCL2 protein overexpression is also different between GCB and ABC subtypes (14,15).Moreover, the predictive significance of some prognostic factors changed following the introduction of a CD20 monoclonal antibody, rituximab, underscores the necessity for revaluating the prognostic value of predictive factors after the introduction of rituximab (7,16).In the present study, we intended to investigate the optimal prognosis cut off value of Ki-67 index in DLBCL patients, and to confirm the specific prognostic value of BCL2 and its association with cell of origin classification (CO...

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Section: Discussionmentioning

confidence: 99%

BCL2/Ki-67 index predict survival in germinal center B-cell-like diffuse large B-cell lymphoma

Tang

Zhou

Cheng³

et al. 2017

Oncology Letters

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“…1B), which is frequently coexpressed with BCL-2 in DLBCL patient samples and cell lines (63). BCL-2 and MCL-1 dependent subgroups can be identified by pharmacological targeting of the two proteins (64). Single-agent treatment with venetoclax was found to induce only modest antitumor activity against certain DLBCL cell lines and resulted in a compensatory increase in expression of MCL-1 (63).…”

Section: Identifying Sensitive Tumor Types and Likely Respondersmentioning

confidence: 99%

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

Sampath²,

et al. 2017

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Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high priority goal for cancer therapy. After decades of effort, drug discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL-2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL-2 biology, were essential to the development of BH3 mimetics such as the BCL-2-selective inhibitor venetoclax. We review a number of preclinical studies that have deepened our understanding of BCL-2 biology and facilitated the clinical development of venetoclax.

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“…76 Another study also showed that concurrent inhibition of BCL-2 and MCL-1 with ABT-199 and homoharringtonine, a plant alkaloid, could induce significant synthetic lethality in most BCL-2-expressing DLBCL cell lines. 77 MCL-1 is widely and highly expressed in MM, and it is also an attractive therapeutic target. 78 Recently, a novel MCL-1 inhibitor S63845 was reported to be tolerable and effective in diverse cancer models, 35 making it possible to overcome venetoclax resistance in various types of B-cell lymphoid malignancies.…”

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confidence: 99%

Development of venetoclax for therapy of lymphoid malignancies

Zhu

Almasan

2017

DDDT

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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.

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Targeting of BCL2 Family Proteins with ABT-199 and Homoharringtonine Reveals BCL2- and MCL1-Dependent Subgroups of Diffuse Large B-Cell Lymphoma

Cited by 80 publications

References 24 publications

BCL2/Ki-67 index predict survival in germinal center B-cell-like diffuse large B-cell lymphoma

BCL2/Ki-67 index predict survival in germinal center B-cell-like diffuse large B-cell lymphoma

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

Development of venetoclax for therapy of lymphoid malignancies

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