Targeting BCL2 for the Treatment of Lymphoid Malignancies

Anderson, Mary Ann; Huang, David C.S.; Roberts, Andrew W.

doi:10.1053/j.seminhematol.2014.05.008

Cited by 137 publications

(117 citation statements)

References 43 publications

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“…Additionally, Bcl-2 family members are also considered in cancer therapy due to their therapeutic potentials [83]. In the clinical trials, the BH3-only mimetic agents targeting Bcl-2 are being investigated in order to find alternative potent therapeutic approaches in several types of malignancies [84][85][86].…”

Section: Bcl-2 Family Membersmentioning

confidence: 99%

Major apoptotic mechanisms and genes involved in apoptosis

et al. 2016

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As much as the cellular viability is important for the living organisms, the elimination of unnecessary or damaged cells has the opposite necessity for the maintenance of homeostasis in tissues, organs and the whole organism. Apoptosis, a type of cell death mechanism, is controlled by the interactions between several molecules and responsible for the elimination of unwanted cells from the body. Apoptosis can be triggered by intrinsically or extrinsically through death signals from the outside of the cell. Any abnormality in apoptosis process can cause various types of diseases from cancer to auto-immune diseases. Different gene families such as caspases, inhibitor of apoptosis proteins, B cell lymphoma (Bcl)-2 family of genes, tumor necrosis factor (TNF) receptor gene superfamily, or p53 gene are involved and/or collaborate in the process of apoptosis. In this review, we discuss the basic features of apoptosis and have focused on the gene families playing critical roles, activation/inactivation mechanisms, upstream/downstream effectors, and signaling pathways in apoptosis on the basis of cancer studies. In addition, novel apoptotic players such as miRNAs and sphingolipid family members in various kind of cancer are discussed.

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Section: Bcl-2 Family Membersmentioning

confidence: 99%

Major apoptotic mechanisms and genes involved in apoptosis

et al. 2016

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“…The first-in-class BCL2 inhibitor, navitoclax, which is an inhibitor of BCL2, BCLx, and BCLw, was tested. 21 However, the development of navitoclax was postponed because of associated severe thrombocytopenia. In contrast, venetoclax (ABT-199), another selective inhibitor of BCL2, was not associated with thrombocytopenia.…”

Section: Strategies For Refractory Patientsmentioning

confidence: 99%

Diffuse large B-cell lymphoma: R-CHOP failure—what to do?

2016

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Although rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard treatment for patients with diffuse large B-cell lymphoma (DLBCL),~30% to 50% of patients are not cured by this treatment, depending on disease stage or prognostic index. Among patients for whom R-CHOP therapy fails, 20% suffer from primary refractory disease (progress during or right after treatment) whereas 30% relapse after achieving complete remission (CR). Currently, there is no good definition enabling us to identify these 2 groups upon diagnosis. Most of the refractory patients exhibit double-hit lymphoma (MYC-BCL2 rearrangement) or double-protein-expression lymphoma (MYC-BCL2 hyperexpression) which have a more aggressive clinical picture. New strategies are currently being explored to obtain better CR rates and fewer relapses. Although young relapsing patients are treated with high-dose therapy followed by autologous transplant, there is an unmet need for better salvage regimens in this setting. To prevent relapse, maintenance therapy with immunomodulatory agents such as lenalidomide is currently undergoing investigation. New drugs will most likely be introduced over the next few years and will probably be different for relapsing and refractory patients. Learning Objectives• To be able to determine at diagnosis which DLBCL patients will likely experience treatment failure with R-CHOP • To understand the mechanisms that underlie resistance to standard treatments • To be able to assess the new proposed drugs, along with their efficacy for specific lymphoma populations such as those with double-hit lymphoma or double-protein-expression lymphoma • To learn more about potential solutions for refractory or relapsing patients

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“…This led to the development of BH3 mimetic agents that antagonize BCL2. 39 Venetoclax is an oral, selective BCL2 inhibitor. It is FDA approved for treatment of R/R del(17p) CLL.…”

Section: Bcl2 Inhibitors In Cllmentioning

confidence: 99%

Current and Emerging Drug Therapies in Chronic Lymphocytic Leukemia

Sethi¹,

Reddy²

2017

Oncology &Amp; Hematology Review (US)

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U ntil recently, chemoimmunotherapy has been the mainstay of treatment approach in chronic lymphocytic leukemia (CLL) patients requiring intervention. With the emergence of targeted treatments, there has been a shift in CLL therapy. With a better understanding of disease biology and risk stratification, a tailored approach based on patient age and comorbidities has evolved over time. The development of new and potent, next generation CD20 antibodies has refined therapy options especially for elderly unfit patients. Furthermore, agents targeting important pathways involved in proliferation and survival of CLL cells including B-cell receptor (BCR) signaling have provided additional treatment options in traditionally chemo-refractory CLL. Given the rapidly expanding repertoire of drugs, current research is focused on optimizing treatment sequence, duration of treatment and assessing long-term toxicities. Several immune mediated therapies are emerging and new combinations are being tested to re-establish antitumor immune effector response in CLL. While embracing the advances in CLL therapy, a few longstanding lessons remain. There is still little role of treatment of asymptomatic individuals. This review presents an overview of current and emerging drug therapies in the rapidly changing area of CLL treatment. Keywords CLL, novel agents, targeted therapyDisclosure: Tarsheen K Sethi and Nishitha M Reddy have nothing to disclose in relation to this article. No funding was received for the publication of this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. In those that meet criteria for treatment, important considerations include: patient age, performance status, comorbidities, and presence of chromosomal aberrations. Recent advancements in the understanding of disease biology have highlighted the importance of several potentially targetable pathways contributing to disease pathogenesis such as aberrant activation of BCR signaling pathway, anti-apoptotic BCL2 pathway, and the role of the microenvironment. These novel agents have expanded the repertoire for patients ineligible for chemoimmunotherapy (CIT) due to age or comorbidities and those with poorly responsive disease (high risk genomics such as del [17p]).This review aims to outline the role of standard CIT, targeted agents and ongoing studies of novel agents defining the present landscape of CLL drug treatment. Currently approved therapies and general tr...

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Targeting BCL2 for the Treatment of Lymphoid Malignancies

Cited by 137 publications

References 43 publications

Major apoptotic mechanisms and genes involved in apoptosis

Major apoptotic mechanisms and genes involved in apoptosis

Diffuse large B-cell lymphoma: R-CHOP failure—what to do?

Current and Emerging Drug Therapies in Chronic Lymphocytic Leukemia

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