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Abt-199

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https://www.readbyqxmd.com/read/29016820/selective-bcl-xl-inhibition-promotes-apoptosis-in-combination-with-mln8237-in-medulloblastoma-and-pediatric-glioblastoma-cells
#1
Jane Levesley, Lynette Steele, Anke Brüning-Richardson, Adam Davison, Jia Zhou, Chunyong Ding, Sean Lawler, Susan C Short
Background: CNS tumors, including medulloblastoma and pediatric glioblastoma (pGBM) account for the majority of solid pediatric malignancies. There remains an unmet need to identify novel treatment approaches in poor prognosis and relapsed pediatric brain tumors, where therapeutic options are limited. Small-molecule B-cell lymphoma 2 (BCL-2) family inhibitors may enhance tumor cell killing when combined with conventional and targeted chemotherapeutic agents. We investigated the effect of disrupting BCL-2 and B cell lymphoma-extra large (BCL-XL) protein function using ABT-263, ABT-199 and WEHI-539 in medulloblastoma and pGBM cells following treatment with MLN8237, an Aurora kinase inhibitor under investigation as a novel agent for the treatment of malignant brain tumors...
July 20, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28984869/bcl2-and-mir-15-16-from-gene-discovery-to-treatment
#2
REVIEW
Yuri Pekarsky, Veronica Balatti, Carlo M Croce
In 1984, we investigated the t(14;18) chromosomal translocations that frequently occur in patients with follicular lymphoma. We first identified a locus on chromosome 18 involved in these translocations with the chromosome 14 containing the immunoglobulin heavy chain locus. Within this region on chromosome 18, we then discovered a gene that we called BCL2, which was activated by the translocations. Since that time, many studies determined that BCL2 is one of the most important oncogenes involved in cancer by inhibiting apoptosis...
October 6, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28972014/first-in-human-response-of-bcl-2-inhibitor-venetoclax-in-t-cell-prolymphocytic-leukemia
#3
Bernd Boidol, Christoph Kornauth, Emiel van der Kouwe, Nicole Prutsch, Lukas Kazianka, Sinan Gültekin, Gregor Hoermann, Marius E Mayerhoefer, Georg Hopfinger, Alexander Hauswirth, Michael Panny, Marie-Bernadette Aretin, Bernadette Hilgarth, Wolfgang R Sperr, Peter Valent, Ingrid Simonitsch-Klupp, Richard Moriggl, Olaf Merkel, Lukas Kenner, Ulrich Jäger, Stefan Kubicek, Philipp B Staber
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive T-lymphoid malignancy usually refractory to current treatment strategies and associated with a short overall survival. By applying next-generation functional testing of primary patient-derived lymphoma cells using a library of 106 FDA-approved anti-cancer drugs or compounds currently in clinical development we pursued to identify novel effective treatments for T-PLL patients. We found that the BCL-2 inhibitor venetoclax (ABT-199) demonstrated the strongest T-PLL specific response when comparing individual ex vivo drug response in 86 patients with refractory hematologic malignancies...
September 27, 2017: Blood
https://www.readbyqxmd.com/read/28947136/bcl-xl-selective-bh3-mimetic-sensitizes-rhabdomyosarcoma-cells-to-chemotherapeutics-by-activation-of-the-mitochondrial-pathway-of-apoptosis
#4
Sara Fatima Faqar-Uz-Zaman, Ulrike Heinicke, Michael Meister, Meike Vogler, Simone Fulda
BH3 mimetics are a promising new class of anticancer agents that inhibit antiapoptotic BCL-2 proteins. Here, we report that BH3 mimetics selectively targeting BCL-xL, BCL-2 or MCL-1 (i.e. A-1331852, ABT-199, A-1210477) act in concert with multiple chemotherapeutic agents (i.e. vincristine (VCR), etoposide (ETO), doxorubicin, actinomycin D and cyclophosphamide) to induce apoptosis in rhabdomyosarcoma (RMS) cells. Similarly, genetic knockdown of BCL-xL primes RMS cells to VCR- or ETO-induced cell death, highlighting the importance of BCL-xL in mediating chemotherapy resistance in RMS...
September 23, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28915653/dual-targeting-of-mdm2-and-bcl2-as-a-therapeutic-strategy-in-neuroblastoma
#5
Alan Van Goethem, Nurten Yigit, Myrthala Moreno-Smith, Sanjeev A Vasudevan, Eveline Barbieri, Frank Speleman, Jason Shohet, Jo Vandesompele, Tom Van Maerken
Wild-type p53 tumor suppressor activity in neuroblastoma tumors is hampered by increased MDM2 activity, making selective MDM2 antagonists an attractive therapeutic strategy for this childhood malignancy. Since monotherapy in cancer is generally not providing long-lasting clinical responses, we here aimed to identify small molecule drugs that synergize with idasanutlin (RG7388). To this purpose we evaluated 15 targeted drugs in combination with idasanutlin in three p53 wild type neuroblastoma cell lines and identified the BCL2 inhibitor venetoclax (ABT-199) as a promising interaction partner...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28852199/mutant-jak3-phosphoproteomic-profiling-predicts-synergism-between-jak3-inhibitors-and-mek-bcl2-inhibitors-for-the-treatment-of-t-cell-acute-lymphoblastic-leukemia
#6
S Degryse, C E de Bock, S Demeyer, I Govaerts, S Bornschein, D Verbeke, K Jacobs, S Binos, D A Skerrett-Byrne, H C Murray, N M Verrills, P Van Vlierberghe, J Cools, M D Dun
Mutations in the interleukin-7 receptor (IL7R) or the JAK3 kinase occur frequently in T-cell acute lymphoblastic leukemia (T-ALL) and both are able to drive cellular transformation and the development of T-ALL in mouse models. However, the signal transduction pathways downstream of JAK3 mutations remain poorly characterized. Here, we describe the phosphoproteome downstream of the JAK3(L857Q)/(M511I) activating mutations in transformed Ba/F3 lymphocyte cells. Signaling pathways regulated by JAK3 mutants were assessed following acute inhibition of JAK1/JAK3 using the JAK kinase inhibitors ruxolitinib or tofacitinib...
August 30, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28838268/rational-combination-strategies-to-enhance-venetoclax-activity-and-overcome-resistance-in-hematologic-malignancies
#7
Steven Grant
Venetoclax (ABT-199) is a Bcl-2-specific BH3-mimetic that has shown significant promise in certain subtypes of CLL as well as in several other hematologic malignancies. As in the case of essentially all targeted agents, intrinsic or acquired resistance to this agent generally occurs, prompting the search for new strategies capable of circumventing this problem. A logical approach to this challenge involves rational combination strategies designed to disable preexisting or induced compensatory survival pathways...
August 24, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28799432/targeted-therapies-in-acute-myeloid-leukemia-a-focus-on-flt-3-inhibitors-and-abt199
#8
REVIEW
Kiran Naqvi, Marina Konopleva, Farhad Ravandi
Acute myeloid leukemia (AML) remains a therapeutic challenge. Despite ongoing research, the standard therapy for AML has not changed significantly in the past four decades. With the identification of cytogenetic and molecular abnormalities, several promising therapeutic agents are currently being investigated. FLT3 mutation is a well-recognized target seen in 30% of the cytogenetically normal AML. More recently, the BCL2 family of anti-apoptotic proteins have also generated great interest as a therapeutic target...
October 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28750570/identification-of-potential-ibrutinib-combinations-in-hematological-malignancies-using-a-combination-high-throughput-screen
#9
Michael Schaffer, Shalini Chaturvedi, Cuc Davis, Regina Aquino, Emily Stepanchick, Matthias Versele, Yang Liu, Jennifer Yang, Rongzhen Lu, Sriram Balasubramanian
Matrix high-throughput screening (HTS) methods are increasingly employed to rapidly define potential therapeutic drug combinations. We used combination HTS to identify compounds showing synergistic anti-proliferative activity with ibrutinib, an irreversible, small-molecule inhibitor of Bruton's tyrosine kinase. The goal was to identify ibrutinib combinations with maximum synergistic effects in heme malignancy lines, particularly in non-Hodgkin lymphoma including diffuse large B-cell lymphoma (DLBCL). Growth inhibition (GI) was used to measure cell viability; synergy scores characterized strength of synergistic interaction...
July 28, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28741496/targeting-bcl-2-like-proteins-to-kill-cancer-cells
#10
REVIEW
Suzanne Cory, Andrew W Roberts, Peter M Colman, Jerry M Adams
Mutations that impair apoptosis contribute to cancer development and reduce the effectiveness of conventional anti-cancer therapies. These insights and understanding of how the B cell lymphoma (BCL)-2 protein family governs apoptosis have galvanized the search for a new class of cancer drugs that target its pro-survival members by mimicking their natural antagonists, the BCL-2 homology (BH)3-only proteins. Successful initial clinical trials of the BH3 mimetic venetoclax/ABT-199, specific for BCL-2, have led to its recent licensing for refractory chronic lymphocytic leukemia and to multiple ongoing trials for other malignancies...
August 2016: Trends in Cancer
https://www.readbyqxmd.com/read/28738256/p53-and-mitf-bcl-2-identified-as-key-pathways-in-the-acquired-resistance-of-nras-mutant-melanoma-to-mek-inhibition
#11
Ahmad Najem, Mohammad Krayem, François Salès, Nader Hussein, Bassam Badran, Caroline Robert, Ahmad Awada, Fabrice Journe, Ghanem E Ghanem
Activating mutations in Neuroblastoma RAS viral oncogene homolog (NRAS) are found in 15-30% of melanomas and are associated with a poor prognosis. Although MAP kinase kinase (MEK) inhibitors used as single agents showed a limited clinical benefit in patients with NRAS-mutant melanoma due to their rather cytostatic effect and high toxicity, their combination with other inhibitors of pathways known to cooperate with MEK inhibition may maximise their antitumour activity. Similarly, in a context where p53 is largely inactivated in melanoma, hyperexpression of Microphthalmia associated transcription factor (MITF) and its downstream anti-apoptotic targets may be the cause of the restraint cytotoxic effects of MEK inhibitors...
September 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28723622/dual-targeting-of-mdm2-and-bcl2-as-a-therapeutic-strategy-in-neuroblastoma
#12
Alan Van Goethem, Nurten Yigit, Myrthala Moreno-Smith, Sanjeev A Vasudevan, Eveline Barbieri, Frank Speleman, Jason Shohet, Jo Vandesompele, Tom Van Maerken
Wild-type p53 tumor suppressor activity in neuroblastoma tumors is hampered by increased MDM2 activity, making selective MDM2 antagonists an attractive therapeutic strategy for this childhood malignancy. Since monotherapy in cancer is generally not providing long-lasting clinical responses, we here aimed to identify small molecule drugs that synergize with idasanutlin (RG7388). To this purpose we evaluated 15 targeted drugs in combination with idasanutlin in three p53 wild type neuroblastoma cell lines and identified the BCL2 inhibitor venetoclax (ABT-199) as a promising interaction partner...
July 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28714472/targeting-the-differential-addiction-to-anti-apoptotic-bcl-2-family-for-cancer-therapy
#13
Akane Inoue-Yamauchi, Paul S Jeng, Kwanghee Kim, Hui-Chen Chen, Song Han, Yogesh Tengarai Ganesan, Kota Ishizawa, Sylvia Jebiwott, Yiyu Dong, Maria C Pietanza, Matthew D Hellmann, Mark G Kris, James J Hsieh, Emily H Cheng
BCL-2 family proteins are central regulators of mitochondrial apoptosis and validated anti-cancer targets. Using small cell lung cancer (SCLC) as a model, we demonstrated the presence of differential addiction of cancer cells to anti-apoptotic BCL-2, BCL-XL or MCL-1, which correlated with the respective protein expression ratio. ABT-263 (navitoclax), a BCL-2/BCL-XL inhibitor, prevented BCL-XL from sequestering activator BH3-only molecules (BH3s) and BAX but not BAK. Consequently, ABT-263 failed to kill BCL-XL-addicted cells with low activator BH3s and BCL-XL overabundance conferred resistance to ABT-263...
July 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28712306/targeting-intrinsic-apoptosis-and-other-forms-of-cell-death-by-bh3-mimetics-in-glioblastoma
#14
REVIEW
Georg Karpel-Massler, Chiaki Tsuge Ishida, Yiru Zhang, Marc-Eric Halatsch, M-Andrew Westhoff, Markus D Siegelin
Novel approaches to treat malignant brain tumors are necessary since these neoplasms still display an unfavorable prognosis. Areas covered: In this review, the authors summarize and analyze recent preclinical data that suggest that targeting intrinsic apoptosis may be a suitable strategy for the treatment of malignant gliomas. They focus on the anti-apoptotic Bcl-2 family members of proteins and the recent drug developments in that field with a special focus on BH3-mimetics. With the discovery of BH3-mimetics that interfere with anti-apoptotic Bcl-2 family members in the low nanomolar range significant excitement has been generated towards these class of inhibitors, such as ABT-737, ABT-263 and the most recent successor, ABT-199 which is most advanced with respect to clinical application...
October 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28691866/safety-and-pharmacodynamics-of-venetoclax-abt-199-in-a-randomized-single-and-multiple-ascending-dose-study-in-women-with-systemic-lupus-erythematosus
#15
P Lu, R Fleischmann, C Curtis, S Ignatenko, S H Clarke, M Desai, S L Wong, K M Grebe, K Black, J Zeng, J Stolzenbach, J K Medema
Objective The anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) may contribute to the pathogenesis of systemic lupus erythematosus. The safety, tolerability, and pharmacodynamics of the selective Bcl-2 inhibitor venetoclax (ABT-199) were assessed in women with systemic lupus erythematosus. Methods A phase 1, double-blind, randomized, placebo controlled study evaluated single ascending doses (10, 30, 90, 180, 300, and 500 mg) and multiple ascending doses (2 cycles; 30, 60, 120, 240, 400, and 600 mg for 1 week, and then 3 weeks off per cycle) of orally administered venetoclax...
January 1, 2017: Lupus
https://www.readbyqxmd.com/read/28670929/exploiting-the-pro-apoptotic-function-of-noxa-as-a-therapeutic-modality-in-cancer
#16
REVIEW
Jeroen E Guikema, Martine Amiot, Eric Eldering
Direct targeting of Bcl-2 members for therapeutic purposes in cancer has become a clinical reality with the FDA approval of ABT-199/Venetoclax. Other highly specific BH3-mimetics are in pre-clinical development. Understanding the functional interactions among the Bcl-2 family is of prime importance to fully exploit their potential. NOXA is considered a rather weak BH3-only member but it has unexplored potential in various settings, which are of relevance in cancer. NOXA is best known as a selective inhibitor of MCL1, itself overexpressed in many cancers, and this protein pair forms an important rheostat in many forms of cell stress...
August 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28646646/antileukemic-activity-and-cellular-effects-of-the-antimalarial-agent-artesunate-in-acute-myeloid-leukemia
#17
Bijender Kumar, Arjun Kalvala, Su Chu, Steven Rosen, Stephen J Forman, Guido Marcucci, Ching-Cheng Chen, Vinod Pullarkat
The artimisinins are a class of antimalarial compounds whose antiparasitic activity is mediated by induction of reactive oxygen species (ROS). Herein, we report that among the artimisinins, artesunate (ARTS), an orally bioavailable compound has the most potent antileukemic activity in AML models and primary patients' blasts. ARTS was most cytotoxic to the FLT3-ITD+ AML MV4-11 and MOLM-13 cells (IC50 values of 1.1 and 0.82μM respectively), inhibited colony formation in primary AML and MDS cells and augmented cytotoxicity of chemotherapeutics...
August 2017: Leukemia Research
https://www.readbyqxmd.com/read/28637496/mir21-sensitized-b-lymphoma-cells-to-abt-199-via-icos-icosl-mediated-interaction-of-treg-cells-with-endothelial-cells
#18
Zhong Zheng, Peng-Peng Xu, Li Wang, Hui-Jin Zhao, Xiang-Qin Weng, Hui-Juan Zhong, Bin Qu, Jie Xiong, Yan Zhao, Xue-Feng Wang, Anne Janin, Wei-Li Zhao
BACKGROUND: MicroRNAs (miRs) are involved in tumor progression by regulating tumor cells and tumor microenvironment. MiR21 is overexpressed in diffuse large B-cell lymphoma (DLBCL) and its biological impact on tumor microenvironment remains unclear. METHODS: MiR21 was assessed by quantitative RT-PCR in patients with newly diagnosed DLBCL. The mechanism of action of miR21 on lymphoma progression and tumor angiogenesis was examined in vitro in B-lymphoma cell lines and in vivo in a murine xenograft model...
June 21, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28578655/potential-mechanisms-of-resistance-to-venetoclax-and-strategies-to-circumvent-it
#19
Stephen K Tahir, Morey L Smith, Paul Hessler, Lisa Roberts Rapp, Kenneth B Idler, Chang H Park, Joel D Leverson, Lloyd T Lam
BACKGROUND: Venetoclax (ABT-199), a first-in-class orally bioavailable BCL-2-selective inhibitor, was recently approved by the FDA for use in patients with 17p-deleted chronic lymphocytic leukemia who have received prior therapy. It is also being evaluated in numerous clinical trials for treating patients with various hematologic malignancies. As with any targeted cancer therapy, it is critically important to identify potential mechanisms of resistance, both for patient stratification and developing strategies to overcome resistance, either before it develops or as it emerges...
June 2, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28468776/vulnerability-of-small-cell-lung-cancer-to-apoptosis-induced-by-the-combination-of-bet-bromodomain-proteins-and-bcl2-inhibitors
#20
Lloyd T Lam, Xiaoyu Lin, Emily J Faivre, Ziping Yang, Xiaoli Huang, Denise M Wilcox, Richard J Bellin, Sha Jin, Stephen K Tahir, Michael Mitten, Terry Magoc, Anahita Bhathena, Warren M Kati, Daniel H Albert, Yu Shen, Tamar Uziel
Ten percent to 15% of all lung cancers are small-cell lung cancer (SCLC). SCLC usually grows and metastasizes before it is diagnosed and relapses rapidly upon treatment. Unfortunately, no new targeted agent has been approved in the past 30 years for patients with SCLC. The BET (bromodomain and extraterminal) proteins bind acetylated histones and recruit protein complexes to promote transcription initiation and elongation. BET proteins have been shown to regulate expression of key genes in oncogenesis, such as MYC, CCND2, and BCL2L1 Here, we demonstrate that approximately 50% of SCLC cell lines are exquisitely sensitive to growth inhibition by the BET inhibitor, ABBV-075...
August 2017: Molecular Cancer Therapeutics
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