keyword
https://read.qxmd.com/read/38437728/targeting-the-tnf-iap-pathway-synergizes-with-anti-cd3-immunotherapy-in-t-cell-acute-lymphoblastic-leukemia
#1
JOURNAL ARTICLE
Andrea Ávila Ávila, Kanokporn Nuantang, Mariana Lobato Oliveira, Sabine Druillennec, Benedetta Zaniboni, Etienne Lengliné, Vahid Asnafi, Jacques Ghysdael, Christine Tran Quang
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Current treatments, based on intensive chemotherapy regimens provide overall survival rates of ~85% in children and <50% in adults, calling the search of new therapeutic options. We previously reported that targeting the T cell receptor (TCR) in T-ALL with anti-CD3 (CD3) mAbs enforces a molecular program akin to thymic negative selection, a major developmental checkpoint in normal T-cell development, induces leukemic cell death and impairs leukemia progression to ultimately improve host survival...
March 4, 2024: Blood
https://read.qxmd.com/read/38412664/xiap-overexpressing-inflammatory-breast-cancer-patients-have-high-infiltration-of-immunosuppressive-subsets-and-increased-tnfr1-signaling-targetable-with-birinapant
#2
JOURNAL ARTICLE
Christophe Van Berckelaer, Steven Van Laere, Seayoung Lee, Michael A Morse, Joseph Geradts, Luc Dirix, Mark Kockx, François Bertucci, Peter Van Dam, Gayathri R Devi
OBJECTIVE: To assess the expression pattern of X-linked inhibitor of apoptosis protein (XIAP), a cellular stress sensor, and delineate the associated changes in the tumor immune microenvironment (TiME) for prognostic value and new therapeutic targets in inflammatory breast cancer (IBC). METHODS: Immunohistochemistry was conducted to assess the spatial localization of immune subsets, XIAP, and PDL1 expression in IBC and non-inflammatory breast cancer (nIBC) pretreatment tumors (n = 142)...
February 26, 2024: Translational Oncology
https://read.qxmd.com/read/38275029/smac-mimetics-for-the-treatment-of-lung-carcinoma-present-development-and-future-prospects
#3
JOURNAL ARTICLE
Ruchi Pandey, Priya Bisht, Pranay Wal, Krishna Murti, V Ravichandiran, Nitesh Kumar
BACKGROUND: Uncontrolled cell growth and proliferation, which originate from lung tissue often lead to lung carcinoma and are more likely due to smoking as well as inhaled environmental toxins. It is widely recognized that tumour cells evade the ability of natural programmed death (apoptosis) and facilitates tumour progression and metastasis. Therefore investigating and targeting the apoptosis pathway is being utilized as one of the best approaches for decades. OBJECTIVE: This review describes the emergence of SMAC mimetic drugs as a treatment approach, its possibilities to synergize the response along with current limitations as well as future perspective therapy for lung cancer...
January 23, 2024: Mini Reviews in Medicinal Chemistry
https://read.qxmd.com/read/38053842/integrating-bulk-and-single-cell-rna-sequencing-data-reveals-epithelial-mesenchymal-transition-molecular-subtype-and-signature-to-predict-prognosis-immunotherapy-efficacy-and-drug-candidates-in-low-grade-gliomas
#4
JOURNAL ARTICLE
Chengcheng Wang, Zheng He
Objective: Epithelial-mesenchymal transition (EMT) is a tightly regulated and dynamic process occurring in both embryonic development and tumor progression. Our study aimed to comprehensively explore the molecular subtypes, immune landscape, and prognostic signature based on EMT-related genes in low-grade gliomas (LGG) in order to facilitate treatment decision-making and drug discovery. Methods: We curated EMT-related genes and performed molecular subtyping with consensus clustering algorithm to determine EMT expression patterns in LGG...
2023: Frontiers in Pharmacology
https://read.qxmd.com/read/37971407/birinapant-selectively-enhances-immunotoxin-mediated-killing-of-cancer-cells-conditional-on-the-iap-protein-levels-within-target-cells
#5
JOURNAL ARTICLE
Antonella Antignani, Maria Teresa Bilotta, Jacob S Roth, Daniel J Urban, Min Shen, Matthew D Hall, David FitzGerald
Immunotoxins (ITs) target cancer cells via antibody binding to surface antigens followed by internalization and toxin-mediated inhibition of protein synthesis. The fate of cells responding to IT treatment depends on the amount and stability of specific pro-apoptotic and pro-survival proteins. When treated with a pseudomonas exotoxin-based immunotoxin (HB21PE40), the triple-negative breast cancer (TNBC) cell line MDA-MB-468 displayed a notable resistance to toxin-mediated killing compared to the epidermoid carcinoma cell line, A431, despite succumbing to the same level of protein synthesis inhibition...
December 2023: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://read.qxmd.com/read/37913914/the-smac-mimetic-birinapant-alleviates-lipopolysaccharide-induced-acute-lung-injury-by-inhibiting-mapk-signaling
#6
JOURNAL ARTICLE
Hui Hu, Man Ma, Tao Li, Li Shi, Peizhi Li
The SMAC mimetic birinapant attenuated liver injury by inhibited the degradation of tumor necrosis factor receptor-associated factor 3 (TRAF3) and activation of MAPK signaling pathway in liver macrophage, but its role in LPS induced acute lung injury (ALI) is not understood. The present study was to investigate the effects of birinapant on ALI and its possible mechanism. A dose of birinapant (30 mg/kg) or a vehicle was administered intravenously 24 hours before LPS (100 μg) stimulation in mice. The levels of TNF-α, IL-6 and IL-1β in bronchoalveolar lavage fluid (BALF) were measured by ELISA...
October 30, 2023: Immunology Letters
https://read.qxmd.com/read/37380559/proteogenomic-characterization-of-bladder-cancer-reveals-sensitivity-to-apoptosis-induced-by-tumor-necrosis-factor-related-apoptosis-inducing-ligand-in-fgfr3-mutated-tumors
#7
JOURNAL ARTICLE
Clarice S Groeneveld, Virginia Sanchez-Quiles, Florent Dufour, Mingjun Shi, Florent Dingli, Rémy Nicolle, Elodie Chapeaublanc, Patrick Poullet, Daniel Jeffery, Clémentine Krucker, Pascale Maillé, Francis Vacherot, Dimitri Vordos, Simone Benhamou, Thierry Lebret, Olivier Micheau, Andrei Zinovyev, Damarys Loew, Yves Allory, Aurélien de Reyniès, Isabelle Bernard-Pierrot, François Radvanyi
BACKGROUND: Molecular understanding of muscle-invasive (MIBC) and non-muscle-invasive (NMIBC) bladder cancer is currently based primarily on transcriptomic and genomic analyses. OBJECTIVE: To conduct proteogenomic analyses to gain insights into bladder cancer (BC) heterogeneity and identify underlying processes specific to tumor subgroups and therapeutic outcomes. DESIGN, SETTING, AND PARTICIPANTS: Proteomic data were obtained for 40 MIBC and 23 NMIBC cases for which transcriptomic and genomic data were already available...
June 27, 2023: European Urology
https://read.qxmd.com/read/37343247/targeting-up-regulated-ciap2-in-sox10-deficient-drug-tolerant-melanoma
#8
JOURNAL ARTICLE
McKenna Q Glasheen, Signe Caksa, Amelia G Young, Nicole A Wilski, Connor A Ott, Inna Chervoneva, Keith T Flaherty, Meenhard Herlyn, Xiaowei Xu, Andrew E Aplin, Claudia Capparelli
Drug tolerance and minimal residual disease (MRD) are likely to prelude acquired resistance to targeted therapy. Mechanisms that allow persister cells to survive in the presence of targeted therapy are being characterized but selective vulnerabilities for these subpopulations remain uncertain. We identified cellular inhibitor of apoptosis protein 2 (cIAP2) as being highly expressed in SOX10-deficient drug tolerant persister (DTP) melanoma cells. Here, we show that cIAP2 is sufficient to induce tolerance to MEK inhibitors, likely by decreasing the levels of cell death...
June 21, 2023: Molecular Cancer Therapeutics
https://read.qxmd.com/read/37304931/definition-and-prognostic-value-of-ph-like-and-ikzf1plus-status-in-children-with-down-syndrome-and-b-cell-precursor-acute-lymphoblastic-leukemia
#9
JOURNAL ARTICLE
Chiara Palmi, Silvia Bresolin, Stefanie Junk, Grazia Fazio, Daniela Silvestri, Marketa Zaliova, Athanasios Oikonomou, Katerina Scharov, Martin Stanulla, Anja Moericke, Martin Zimmermann, Martin Schrappe, Barbara Buldini, Sanil Bhatia, Arndt Borkhardt, Claudia Saitta, Marta Galbiati, Michela Bardini, Luca Lo Nigro, Valentino Conter, Maria Grazia Valsecchi, Andrea Biondi, Geertruy Te Kronnie, Gunnar Cario, Giovanni Cazzaniga
Children with Down syndrome have an augmented risk for B-cell acute lymphoblastic leukemia (DS-ALL), which is associated with lower survival than in non-DS-ALL. It is known that cytogenetic abnormalities common in childhood ALL are less frequent in DS-ALL, while other genetic aberrancies (ie, CRLF2 overexpression and IKZF1 deletions) are increased. A possible cause for the lower survival of DS-ALL that we herewith evaluated for the first time was the incidence and prognostic value of the Philadelphia-like (Ph-like) profile and the IKZF1plus pattern...
June 2023: HemaSphere
https://read.qxmd.com/read/37154878/combined-inhibition-of-xiap-and-autophagy-induces-apoptosis-and-differentiation-in-acute-myeloid-leukaemia
#10
JOURNAL ARTICLE
Ziyang Huang, Jifan Zhou, Yinyan Jiang, Yixiang Han, Xiaofang Wang, Fanfan Li, Songfu Jiang, Kang Yu, Shenghui Zhang
Perturbations in autophagy, apoptosis and differentiation have greatly affected the progression and therapy of acute myeloid leukaemia (AML). The role of X-linked inhibitor of apoptosis (XIAP)-related autophagy remains unclear in AML therapeutics. Here, we found that XIAP was highly expressed and associated with poor overall survival in patients with AML. Furthermore, pharmacologic inhibition of XIAP using birinapant or XIAP knockdown via siRNA impaired the proliferation and clonogenic capacity by inducing autophagy and apoptosis in AML cells...
May 8, 2023: Journal of Cellular and Molecular Medicine
https://read.qxmd.com/read/37132167/the-expanding-role-of-iap-antagonists-for-the-treatment-of-head-and-neck-cancer
#11
REVIEW
Vikash Kansal, Brendan L C Kinney, Srijayaprakash Uppada, Nabil F Saba, William A Stokes, Zachary S Buchwald, Nicole C Schmitt
Inhibitors of apoptosis proteins (IAPs) inhibit the intrinsic and extrinsic cell death pathways, promoting cell survival. Antagonists of these pathways are under study as anti-cancer therapeutics. A high proportion of head and neck squamous cell carcinomas (HNSCCs) have genomic alterations in IAP pathways, resulting in the dysregulation of cell death pathways and rendering them susceptible to IAP antagonist therapy. Preclinical studies suggest IAP antagonists, also known as second mitochondria-derived activator of caspases mimetics, may be effective treatments for HNSCC, especially when combined with radiation...
May 2, 2023: Cancer Medicine
https://read.qxmd.com/read/36831656/smac-mimetics-synergistically-cooperate-with-hdac-inhibitors-enhancing-tnf-%C3%AE-autocrine-signaling
#12
JOURNAL ARTICLE
Yusuke Shibuya, Kei Kudo, Kristen P Zeligs, David Anderson, Lidia Hernandez, Franklin Ning, Christopher B Cole, Maria Fergusson, Noemi Kedei, John Lyons, Jason Taylor, Soumya Korrapati, Christina M Annunziata
The overexpression of inhibitor of apoptosis (IAP) proteins is strongly related to poor survival of women with ovarian cancer. Recurrent ovarian cancers resist apoptosis due to the dysregulation of IAP proteins. Mechanistically, Second Mitochondrial Activator of Caspases (SMAC) mimetics suppress the functions of IAP proteins to restore apoptotic pathways resulting in tumor death. We previously conducted a phase 2 clinical trial of the single-agent SMAC mimetic birinapant and observed minimal drug response in women with recurrent ovarian cancer despite demonstrating on-target activity...
February 18, 2023: Cancers
https://read.qxmd.com/read/36831373/combined-inhibition-of-iaps-and-wee1-enhances-tnf%C3%AE-and-radiation-induced-cell-death-in-head-and-neck-squamous-carcinoma
#13
JOURNAL ARTICLE
Tiffany Toni, Ramya Viswanathan, Yvette Robbins, Sreenivasulu Gunti, Xinping Yang, Angel Huynh, Hui Cheng, Anastasia L Sowers, James B Mitchell, Clint T Allen, Ethan L Morgan, Carter Van Waes
Head and neck squamous cell carcinoma (HNSCC) remains a prevalent diagnosis with current treatment options that include radiotherapy and immune-mediated therapies, in which tumor necrosis factor-α (TNFα) is a key mediator of cytotoxicity. However, HNSCC and other cancers often display TNFα resistance due to activation of the canonical IKK-NFκB/RELA pathway, which is activated by, and induces expression of, cellular inhibitors of apoptosis proteins (cIAPs). Our previous studies have demonstrated that the IAP inhibitor birinapant sensitized HNSCC to TNFα-dependent cell death in vitro and radiotherapy in vivo...
February 6, 2023: Cancers
https://read.qxmd.com/read/36542236/divergent-effect-of-birinapant-and-bv6-smac-mimetic-on-tnf%C3%AE-induced-nf-%C3%AE%C2%BAb-signaling-and-cell-viability-in-activated-hepatic-stellate-cells
#14
JOURNAL ARTICLE
Shaikh Maryam Ghufran, Sachin Sharma, Sampa Ghose, Subhrajit Biswas
BACKGROUND: Tumor necrosis factor-α (TNFα) is a pleiotropic cytokine involved in nuclear factor kappa B (NF-κB) mediated cell survival as well as cell death. High serum TNFα levels correlate with liver fibrosis and enhance hepatic stellate cell (HSC) viability. However, the regulatory role of cellular inhibitor of apoptosis-1/2 (cIAP1/2) during TNFα induced NF-κB signaling in activated HSCs is largely unknown. METHOD AND RESULTS: Activated HSCs were treated with cIAP1/2 inhbitiors i...
December 21, 2022: Molecular Biology Reports
https://read.qxmd.com/read/36531039/combining-the-smac-mimetic-lcl161-with-gemcitabine-plus-cisplatin-therapy-inhibits-and-prevents-the-emergence-of-multidrug-resistance-in-cholangiocarcinoma
#15
JOURNAL ARTICLE
Sunisa Prasopporn, Orawan Suppramote, Ben Ponvilawan, Chanette Jamyuang, Jantappapa Chanthercrob, Amphun Chaiboonchoe, Pimkanya More-Krong, Kamonchanok Kongsri, Monthira Suntiparpluacha, Rawisak Chanwat, Krittiya Korphaisarn, Seiji Okada, Somponnat Sampattavanich, Siwanon Jirawatnotai
Cholangiocarcinoma (CCA) is a highly lethal gastrointestinal malignancy that has one of the worst prognoses among solid tumors. The combination of Gemcitabine + Cisplatin (GEM/CIS) remains the standard first-line treatment for advanced stage CCA. However, this drug combination yields only a modest objective response rate, and in cases that initially respond to this treatment, drug resistance commonly rapidly develops. To improve the efficiency of GEM/CIS therapy for CCA, a thorough understanding of the mechanism of GEM/CIS resistance in CCA is required...
2022: Frontiers in Oncology
https://read.qxmd.com/read/36460631/primary-cilia-suppress-ripk3-mediated-necroptosis
#16
JOURNAL ARTICLE
Emilia Kieckhöfer, Gisela G Slaats, Lena K Ebert, Marie-Christine Albert, Claudia Dafinger, Hamid Kashkar, Thomas Benzing, Bernhard Schermer
Cilia are sensory organelles that project from the surface of almost all cells. Nephronophthisis (NPH) and NPH-related ciliopathies are degenerative genetic diseases caused by mutation of cilia-associated genes. These kidney disorders are characterized by progressive loss of functional tubular epithelial cells which is associated with inflammation, progressive fibrosis, and cyst formation, ultimately leading to end-stage renal disease. However, disease mechanisms remain poorly understood. Here, we show that targeted deletion of cilia in renal epithelial cells enhanced susceptibility to necroptotic cell death under inflammatory conditions...
December 2, 2022: Cell Death Discovery
https://read.qxmd.com/read/36458202/the-iap-antagonist-birinapant-enhances-chimeric-antigen-receptor-t%C3%A2-cell-therapy-for-glioblastoma-by-overcoming-antigen-heterogeneity
#17
JOURNAL ARTICLE
Edward Z Song, Xin Wang, Benjamin I Philipson, Qian Zhang, Radhika Thokala, Logan Zhang, Charles-Antoine Assenmacher, Zev A Binder, Guo-Li Ming, Donald M O'Rourke, Hongjun Song, Michael C Milone
Antigen heterogeneity that results in tumor antigenic escape is one of the major obstacles to successful chimeric antigen receptor (CAR) T cell therapies in solid tumors including glioblastoma multiforme (GBM). To address this issue and improve the efficacy of CAR T cell therapy for GBM, we developed an approach that combines CAR T cells with inhibitor of apoptosis protein (IAP) antagonists, a new class of small molecules that mediate the degradation of IAPs, to treat GBM. Here, we demonstrated that the IAP antagonist birinapant could sensitize GBM cell lines and patient-derived primary GBM organoids to apoptosis induced by CAR T cell-derived cytokines, such as tumor necrosis factor...
December 15, 2022: Molecular Therapy Oncolytics
https://read.qxmd.com/read/35941108/interaction-of-lats1-with-smac-links-the-mst2-hippo-pathway-with-apoptosis-in-an-iap-dependent-manner
#18
JOURNAL ARTICLE
Lucía García-Gutiérrez, Emma Fallahi, Nourhan Aboud, Niall Quinn, David Matallanas
Metastatic malignant melanoma is the deadliest skin cancer, and it is characterised by its high resistance to apoptosis. The main melanoma driving mutations are part of ERK pathway, with BRAF mutations being the most frequent ones, followed by NRAS, NF1 and MEK mutations. Increasing evidence shows that the MST2/Hippo pathway is also deregulated in melanoma. While mutations are rare, MST2/Hippo pathway core proteins expression levels are often dysregulated in melanoma. The expression of the tumour suppressor RASSF1A, a bona fide activator of the MST2 pathway, is silenced by promoter methylation in over half of melanomas and correlates with poor prognosis...
August 8, 2022: Cell Death & Disease
https://read.qxmd.com/read/35676324/rb-loss-determines-selective-resistance-and-novel-vulnerabilities-in-er-positive-breast-cancer-models
#19
JOURNAL ARTICLE
Vishnu Kumarasamy, Ram Nambiar, Jianxin Wang, Hanna Rosenheck, Agnieszka K Witkiewicz, Erik S Knudsen
The management of metastatic estrogen receptor (ER) positive HER2 negative breast cancer (ER+) has improved; however, therapeutic resistance and disease progression emerges in majority of cases. Using unbiased approaches, as expected PI3K and MTOR inhibitors emerge as potent inhibitors to delay proliferation of ER+ models harboring PIK3CA mutations. However, the cytostatic efficacy of these drugs is hindered due to marginal impact on the expression of cyclin D1. Different combination approaches involving the inhibition of ER pathway or cell cycle result in durable growth arrest via RB activation and subsequent inhibition of CDK2 activity...
July 2022: Oncogene
https://read.qxmd.com/read/34714906/a-nanodrug-incorporating-sirna-pd-l1-and-birinapant-for-enhancing-tumor-immunotherapy
#20
JOURNAL ARTICLE
Tingting Gong, Yujun Cai, Fengze Sun, Jiaxin Chen, Zhongzhen Su, Xintao Shuai, Hong Shan
Triple-negative breast cancer (TNBC) is associated with a worse prognosis and higher mortality than other breast cancers, and intensive effort has been made to develop therapies targeting TNBC. TNBC shows higher expression levels of programmed cell death ligand 1 (PD-L1) than other breast cancer types, which leads to a decrease in the killing effects of CD8+ T cells in the tumor microenvironment. Inhibitors of apoptosis proteins (IAPs) could prevent cell death through suppressing caspase activity. Here, Birinapant, an antagonist of IAPs, was found to promote the tumor infiltration of CD8+ T cells via increasing the secretion of the chemokine CXCL9...
November 23, 2021: Biomaterials Science
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