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https://www.readbyqxmd.com/read/27907031/in-vitro-pre-clinical-validation-of-suicide-gene-modified-anti-cd33-redirected-chimeric-antigen-receptor-t-cells-for-acute-myeloid-leukemia
#1
Kentaro Minagawa, Muhammad O Jamil, Mustafa Al-Obaidi, Larisa Pereboeva, Donna Salzman, Harry P Erba, Lawrence S Lamb, Ravi Bhatia, Shin Mineishi, Antonio Di Stasi
BACKGROUND: Approximately fifty percent of patients with acute myeloid leukemia can be cured with current therapeutic strategies which include, standard dose chemotherapy for patients at standard risk of relapse as assessed by cytogenetic and molecular analysis, or high-dose chemotherapy with allogeneic hematopoietic stem cell transplant for high-risk patients. Despite allogeneic hematopoietic stem cell transplant about 25% of patients still succumb to disease relapse, therefore, novel strategies are needed to improve the outcome of patients with acute myeloid leukemia...
2016: PloS One
https://www.readbyqxmd.com/read/27806433/targeting-bcl2-with-bh3-mimetics-basic-science-and-clinical-application-of-venetoclax-in-cll-and-related-b-cell-malignancies
#2
Andrew W Roberts, David C S Huang
The intracellular protein B-cell-lymphoma-2 (BCL2) has been considered an attractive target for cancer therapy since the discovery of its function as a major promoter of cell survival (an anti-apoptotic) in the late 1980s. However, the challenges of targeting a protein-protein interaction delayed the discovery of fit-for-purpose molecules until the mid-2000s. Since then, a series of high affinity small organic molecules that inhibits the interaction of BCL2 with the apoptotic machinery, the so-called BH3-mimetics, have been developed...
November 2, 2016: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27725868/synergistic-anti-leukemic-interactions-between-abt-199-and-panobinostat-in-acute-myeloid-leukemia-ex-vivo
#3
Jonathan Schwartz, Xiaojia Niu, Eric Walton, Laura Hurley, Hai Lin, Holly Edwards, Jeffrey W Taub, Zhihong Wang, Yubin Ge
Cure rates for acute myeloid leukemia (AML) remain suboptimal; thus new treatment strategies are needed for this deadly disease. Poor clinical outcomes have been associated with overexpression of the anti-apoptotic Bcl-2 family proteins Bcl-2, Bcl-xL, and Mcl-1, which have garnered great interest as therapeutic targets. While the Bcl-2-selective inhibitor ABT-199 has demonstrated promising preclinical anti-leukemic activities, intrinsic drug resistance remains a problem. In our most recent study, we identified Mcl-1 sequestration of Bim as a mechanism of intrinsic resistance to ABT-199 in AML cells, thus upregulating Bim could overcome such resistance...
2016: American Journal of Translational Research
https://www.readbyqxmd.com/read/27722045/bcl-2-inhibition-impairs-mitochondrial-function-and-targets-oral-tongue-squamous-cell-carcinoma
#4
Lei Xiong, Yi Tang, Zhaoyang Liu, Jing Dai, Xiaozhou Wang
PURPOSE: To understand the role of Bcl-2 overexpression in oral tongue squamous cell carcinoma (OTSCC) patients and investigate the efficacy of targeting Bcl-2 in OTSCC. METHODS: The expression level of Bcl-2 on normal tongue cells and OTSCC cells were measured by real-time PCR and western blotting. The functional roles of Bcl-2 were examined by MTS, flow cytometry and xenograft cancer mouse model. Mechanism studies were performed by analyzing mitochondrial functions in a panel of OTSCC cell lines...
2016: SpringerPlus
https://www.readbyqxmd.com/read/27695617/the-potential-of-venetoclax-abt-199-in-chronic-lymphocytic-leukemia
#5
Gilad Itchaki, Jennifer R Brown
Venetoclax (VEN, ABT-199/GDC-0199) is an orally bioavailable BH3-mimetic that specifically inhibits the anti-apoptotic B-cell lymphoma/leukemia 2 (BCL2) protein. Although BCL2 overexpression is not genetically driven in chronic lymphocytic leukemia (CLL), it is nearly universal and represents a highly important and prevalent mechanism of apoptosis evasion, making it an attractive therapeutic target. This review summarizes the role of BCL2 in CLL pathogenesis, the development path targeting its inhibition prior to VEN, and the preclinical and clinical data regarding the effectiveness and safety of VEN...
October 2016: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/27661108/acquired-resistance-to-venetoclax-abt-199-in-t-14-18-positive-lymphoma-cells
#6
Juraj Bodo, Xiaoxian Zhao, Lisa Durkin, Andrew J Souers, Darren C Phillips, Mitchell R Smith, Eric D Hsi
The chromosomal translocation t(14;18) in follicular lymphoma (FL) is a primary oncogenic event resulting in BCL-2 over-expression. This study investigates activity of the BH3 mimetic venetoclax (ABT-199), which targets BCL-2, and mechanisms of acquired resistance in FL.The sensitivity of FL cells to venetoclax treatment correlated with BCL-2/BIM ratio. Cells with similar expression of anti-apoptotic proteins, but with higher levels of BIM were more sensitive to the treatment. Venetoclax induced dissociation of BCL-2/ BIM complex and a decrease in mitochondrial potential...
September 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27617850/selective-covalent-targeting-of-anti-apoptotic-bfl-1-by-cysteine-reactive-stapled-peptide-inhibitors
#7
Annissa J Huhn, Rachel M Guerra, Edward P Harvey, Gregory H Bird, Loren D Walensky
Anti-apoptotic BCL-2 family proteins block cell death by trapping the critical α-helical BH3 domains of pro-apoptotic members in a surface groove. Cancer cells hijack this survival mechanism by overexpressing a spectrum of anti-apoptotic members, mounting formidable apoptotic blockades that resist chemotherapeutic treatment. Drugging the BH3-binding pockets of anti-apoptotic proteins has become a highest-priority goal, fueled by the clinical success of ABT-199, a selective BCL-2 inhibitor, in reactivating apoptosis in BCL-2-dependent cancers...
September 22, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27586967/venetoclax-does-not-prolong-the-qt-interval-in-patients-with-hematological-malignancies-an-exposure-response-analysis
#8
Kevin J Freise, Martin Dunbar, Aksana K Jones, David Hoffman, Sari L Heitner Enschede, Shekman Wong, Ahmed Hamed Salem
PURPOSE: Venetoclax (ABT-199/GDC-0199) is a selective first-in-class B cell lymphoma-2 inhibitor being developed for the treatment of hematological malignancies. The aim of this study was to determine the potential of venetoclax to prolong the corrected QT (QTc) interval and to evaluate the relationship between systemic venetoclax concentration and QTc interval. METHODS: The study population included 176 male and female patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 105) or non-Hodgkin's lymphoma (n = 71) enrolled in a phase 1 safety, pharmacokinetic, and efficacy study...
October 2016: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/27582059/targeting-bcl-2-and-abl-lyn-in-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia
#9
Jessica T Leonard, Joelle S J Rowley, Christopher A Eide, Elie Traer, Brandon Hayes-Lattin, Marc Loriaux, Stephen E Spurgeon, Brian J Druker, Jeffrey W Tyner, Bill H Chang
Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) remains a challenge. Although the addition of targeted tyrosine kinase inhibitors (TKIs) to standard cytotoxic therapy has greatly improved upfront treatment, treatment-related morbidity and mortality remain high. TKI monotherapy provides only temporary responses and renders patients susceptible to the development of TKI resistance. Thus, identifying agents that could enhance the activity of TKIs is urgently needed. Recently, a selective inhibitor of B cell lymphoma 2 (BCL-2), ABT-199 (venetoclax), has shown impressive activity against hematologic malignancies...
August 31, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27569395/antitumor-action-of-cdk-inhibitor-ls-007-as-a-single-agent-and-in-combination-with-abt-199-against-human-acute-leukemia-cells
#10
Shao Xie, Hui Jiang, Xiao-Wen Zhai, Fan Wei, Shu-Dong Wang, Jian Ding, Yi Chen
AIM: LS-007 is a CDK inhibitor, which exhibits potent antitumor activity against chronic lymphocytic leukemia and ovarian cancer cells. In this study, we further evaluated the antitumor activity of LS-007 alone and in combination with a Bcl-2 inhibitor ABT-199 in acute leukemia (AL) cells. METHODS: Cell viability was detected using resazurin assay, and cell apoptosis was examined using Annexin V/PI double staining and flow cytometry. The inhibition of LS-007 on kinases was evaluated with the mobility shift assay or ELISA...
November 2016: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/27535975/bcl2-inhibitors-as-anticancer-drugs-a-plethora-of-misleading-bh3-mimetics
#11
REVIEW
Ryan S Soderquist, Alan Eastman
Antiapoptotic BCL2 proteins play a major role in tumor cell survival. Hence, BCL2 inhibitors have been developed as direct inducers of apoptosis. ABT-199 (venetoclax) received breakthrough therapy designation from the FDA due to its apparent efficacy in CLL and AML. However, resistance to ABT-199 is mediated by other BCL2 proteins including BCLXL and MCL1. Considerable effort has been expended seeking novel "BH3 mimetics" that inhibit all of these BCL2 proteins. While many BH3 mimetics inhibit BCL2 proteins in vitro, they fail to directly inhibit them in intact cells...
September 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27520705/iap-antagonists-birinapant-and-at-406-efficiently-synergise-with-either-trail-braf-or-bcl-2-inhibitors-to-sensitise-brafv600e-colorectal-tumour-cells-to-apoptosis
#12
Philippos Perimenis, Apostolos Galaris, Alexandra Voulgari, Margarita Prassa, Alexander Pintzas
BACKGROUND: High expression levels of Inhibitors of Apoptosis Proteins (IAPs) have been correlated with poor cancer prognosis and block the cell death pathway by interfering with caspase activation. SMAC-mimetics are small-molecule inhibitors of IAPs that mimic the endogenous SMAC and promote the induction of cell death by neutralizing IAPs. METHODS: In this study, anti-tumour activity of new SMAC-mimetics Birinapant and AT-406 is evaluated against colorectal adenocarcinoma cells and IAP cross-talk with either oncogenic BRAF or BCL-2, or with the TRAIL are further exploited towards rational combined protocols...
2016: BMC Cancer
https://www.readbyqxmd.com/read/27512118/trabectedin-is-active-against-malignant-pleural-mesothelioma-cell-and-xenograft-models-and-synergizes-with-chemotherapy-and-bcl-2-inhibition-in-vitro
#13
Mir A Hoda, Christine Pirker, Yawen Dong, Karin Schelch, Petra Heffeter, Kushtrim Kryeziu, Sushilla van Schoonhoven, Thomas Klikovits, Viktoria Laszlo, Anita Rozsas, Judit Ozsvar, Walter Klepetko, Balazs Döme, Michael Grusch, Balazs Hegedüs, Walter Berger
Malignant pleural mesothelioma (MPM) is characterized by widespread resistance to systemic therapy. Trabectedin is an antineoplastic agent targeting both the malignant cells and the tumor microenvironment that has been approved for the treatment of advanced soft tissue sarcoma and ovarian cancer. In this preclinical study, we evaluated the antineoplastic potential of trabectedin as a single agent and in drug combination approaches in human MPM. Therefore, we utilized an extended panel of MPM cell lines (n = 6) and primary cell cultures from surgical MPM specimens (n = 13), as well as nonmalignant pleural tissue samples (n = 2)...
October 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27499136/hox-gene-expression-predicts-response-to-bcl-2-inhibition-in-acute-myeloid-leukemia
#14
M Kontro, A Kumar, M M Majumder, S Eldfors, A Parsons, T Pemovska, J Saarela, B Yadav, D Malani, Y Fløisand, M Höglund, K Remes, B T Gjertsen, O Kallioniemi, K Wennerberg, C A Heckman, K Porkka
Inhibitors of BCL-2 such as venetoclax (ABT-199) and navitoclax (ABT-263) are clinically explored in several cancer types, including acute myeloid leukemia (AML), to selectively induce apoptosis in cancer cells. To identify robust biomarkers for BCL-2 inhibitor sensitivity, we evaluated the ex vivo sensitivity of fresh leukemic cells from 73 diagnosed and relapsed/refractory AML patients, then comprehensively assessed if the responses correlated to specific mutations or gene expression signatures. Compared to samples from healthy donor controls (non-sensitive) and chronic lymphocytic leukemia (CLL) patients (highly-sensitive), AML samples exhibited variable responses to BCL-2 inhibition...
August 8, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27494888/the-trans-membrane-domain-of-bcl-2%C3%AE-but-not-its-hydrophobic-cleft-is-a-critical-determinant-for-efficient-ip3-receptor-inhibition
#15
Hristina Ivanova, Abigael Ritane, Larry Wagner, Tomas Luyten, George Shapovalov, Kirsten Welkenhuyzen, Bruno Seitaj, Giovanni Monaco, Humbert De Smedt, Natalia Prevarskaya, David I Yule, Jan B Parys, Geert Bultynck
The anti-apoptotic Bcl-2 protein is emerging as an efficient inhibitor of IP3R function, contributing to its oncogenic properties. Yet, the underlying molecular mechanisms remain not fully understood. Using mutations or pharmacological inhibition to antagonize Bcl-2's hydrophobic cleft, we excluded this functional domain as responsible for Bcl-2-mediated IP3Rs inhibition. In contrast, the deletion of the C-terminus, containing the trans-membrane domain, which is only present in Bcl-2α, but not in Bcl-2β, led to impaired inhibition of IP3R-mediated Ca2+ release and staurosporine-induced apoptosis...
August 2, 2016: Oncotarget
https://www.readbyqxmd.com/read/27471867/new-investigational-drugs-with-single-agent-activity-in-multiple-myeloma
#16
REVIEW
A M Rajan, S Kumar
The treatment of multiple myeloma (MM) is rapidly evolving. In the United States, four drugs (panobinostat, ixazomib, daratumumab and elotuzumab) were approved for the treatment of MM in 2015. As a result of improved diagnosis and therapy, there has been a dramatic improvement in the outcome of MM in the last decade, probably more than any other malignancy. Numerous agents continue to be studied in preclinical models and in clinical trials, with many demonstrating clinical efficacy that appears promising enough to have a trajectory for regulatory approval...
July 29, 2016: Blood Cancer Journal
https://www.readbyqxmd.com/read/27469405/pro-survival-signal-inhibition-by-cdk-inhibitor-dinaciclib-in-chronic-lymphocytic-leukaemia
#17
Yixiang Chen, Sandra Germano, Chris Clements, Jesvin Samuel, Ghalia Shelmani, Sandrine Jayne, Martin J S Dyer, Salvador Macip
Dinaciclib is a cyclin-dependent kinase inhibitor with clinical potential in different cancers, including chronic lymphocytic leukaemia (CLL). In order to better understand its cytotoxic action, we characterized its effects on signalling pathways important for the survival of CLL cells. We found that dinaciclib induced apoptosis through the activation of caspases 8 and 9, which was independent of the presence of cytokines to mimic the environment of proliferation centres or IGVH mutation status. Moreover, treatment with dinaciclib led to the inhibition of oncogenic pathways normally activated in stimulated CLL cells, such as STAT3, NF-κB, p38, PI3K/AKT and RAF/MEK/ERK...
November 2016: British Journal of Haematology
https://www.readbyqxmd.com/read/27357816/expanding-the-armamentarium-for-chronic-lymphocytic-leukemia-a-review-of-novel-agents-in-the-management-of-chronic-lymphocytic-leukemia
#18
Bernard L Marini, Lisa Samanas, Anthony J Perissinotti
Treatment options for chronic lymphocytic leukemia, the most common leukemia in the United States, have expanded rapidly in recent years. While traditional chemoimmunotherapy still remains a mainstay for young, fit patients, a number of novel targeted therapies have emerged that have changed the therapeutic landscape. Two innovative anti-CD20 monoclonal antibodies, obinutuzumab and ofatumomamab, have demonstrated activity in chronic lymphocytic leukemia and represent well-tolerated options in upfront management of elderly patients or in those with significant comorbidities...
June 29, 2016: Journal of Oncology Pharmacy Practice
https://www.readbyqxmd.com/read/27297795/high-content-screening-identifies-kinase-inhibitors-that-overcome-venetoclax-resistance-in-activated-cll-cells
#19
Sina Oppermann, Jarkko Ylanko, Yonghong Shi, Santosh Hariharan, Christopher C Oakes, Patrick M Brauer, Juan C Zúñiga-Pflücker, Brian Leber, David E Spaner, David W Andrews
Novel agents such as the Bcl-2 inhibitor venetoclax (ABT-199) are changing treatment paradigms for chronic lymphocytic leukemia (CLL) but important problems remain. Although some patients exhibit deep and durable responses to venetoclax as a single agent, other patients harbor subpopulations of resistant leukemia cells that mediate disease recurrence. One hypothesis for the origin of resistance to venetoclax is by kinase-mediated survival signals encountered in proliferation centers that may be unique for individual patients...
August 18, 2016: Blood
https://www.readbyqxmd.com/read/27283158/targeting-mcl-1-bcl-xl-forestalls-the-acquisition-of-resistance-to-abt-199-in-acute-myeloid-leukemia
#20
Kevin H Lin, Peter S Winter, Abigail Xie, Cullen Roth, Colin A Martz, Elizabeth M Stein, Grace R Anderson, Jennifer P Tingley, Kris C Wood
ABT-199, a potent and selective small-molecule antagonist of BCL-2, is being clinically vetted as pharmacotherapy for the treatment of acute myeloid leukemia (AML). However, given that prolonged monotherapy tends to beget resistance, we sought to investigate the means by which resistance to ABT-199 might arise in AML and the extent to which those mechanisms might be preempted. Here we used a pathway-activating genetic screen to nominate MCL-1 and BCL-XL as potential nodes of resistance. We then characterized a panel of ABT-199-resistant myeloid leukemia cell lines derived through chronic exposure to ABT-199 and found that acquired drug resistance is indeed driven by the upregulation of MCL-1 and BCL-XL...
2016: Scientific Reports
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