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Your search keyword '"Valeria Voevoda-Dimenshtein"' showing total 3 results
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3 results on '"Valeria Voevoda-Dimenshtein"'

1. CXCL13 chemokine is a novel player in multiple myeloma osteolytic microenvironment, M2 macrophage polarization, and tumor progression

Author

Katia Beider, Valeria Voevoda-Dimenshtein, Ali Zoabi, Evgenia Rosenberg, Hila Magen, Olga Ostrovsky, Avichai Shimoni, Lola Weiss, Michal Abraham, Amnon Peled, and Arnon Nagler

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background We assessed the mechanism by which multiple myeloma (MM) shapes the bone marrow (BM) microenvironment and affects MΦ polarization. Methods In vivo xenograft model of BM-disseminated human myeloma, as well as analysis of MM cell lines, stromal components, and primary samples from patients with MM, was utilized. Results Analysis of the BM from MM-bearing mice inoculated with human CXCR4-expressing RPMI8226 cells revealed a significant increase in M2 MΦ cell numbers (p

Published
2022
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2. Molecular and Functional Signatures Associated with CAR T Cell Exhaustion and Impaired Clinical Response in Patients with B Cell Malignancies

Author

Katia Beider, Orit Itzhaki, Jacob Schachter, Ania Hava Grushchenko-Polaq, Valeria Voevoda-Dimenshtein, Evgenia Rosenberg, Olga Ostrovsky, Olivia Devillers, Ronnie Shapira Frommer, Li-at Zeltzer, Amos Toren, Elad Jacoby, Avichai Shimoni, Abraham Avigdor, Arnon Nagler, and Michal J. Besser

Subjects
CAR T, B cell malignancies, exhaustion, resistance, molecular signature, Cytology, QH573-671
Abstract

Despite the high rates of complete remission following chimeric antigen receptor (CAR) T cell therapy, its full capacity is currently limited by the generation of dysfunctional CAR T cells. Senescent or exhausted CAR T cells possess poor targeting and effector functions, as well as impaired cell proliferation and persistence in vivo. Strategies to detect, prevent or reverse T cell exhaustion are therefore required in order to enhance the effectiveness of CAR T immunotherapy. Here we report that CD19 CAR T cells from non-responding patients with B cell malignancies show enrichment of CD8+ cells with exhausted/senescent phenotype and display a distinct transcriptional signature with dysregulation of genes associated with terminal exhaustion. Furthermore, CAR T cells from non-responding patients exhibit reduced proliferative capacity and decreased IL-2 production in vitro, indicating functional impairment. Overall, our work reveals potential mediators of resistance, paving the way to studies that will enhance the efficacy and durability of CAR T therapy in B cell malignancies.

Published
2022
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3. The mTOR inhibitor everolimus overcomes CXCR4-mediated resistance to histone deacetylase inhibitor panobinostat through inhibition of p21 and mitotic regulators

Author

Lola Weiss, Valeria Voevoda-Dimenshtein, Avichai Shimoni, Evgenia Rosenberg, Jonathan Canaani, Michal Abraham, Amnon Peled, Hila Magen, Yaarit Sirovsky, Arnon Nagler, Olga Ostrovsky, Noya Shilo, Katia Beider, Michael Milyavsky, and Hanna Bitner

Subjects
0301 basic medicine, rho GTP-Binding Proteins, Programmed cell death, Receptors, CXCR4, medicine.drug_class, Mitosis, Antineoplastic Agents, Bone Marrow Cells, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Panobinostat, Cell Line, Tumor, medicine, Animals, Humans, Everolimus, PI3K/AKT/mTOR pathway, Cells, Cultured, Pharmacology, Dose-Response Relationship, Drug, Cell growth, TOR Serine-Threonine Kinases, Histone deacetylase inhibitor, Cell cycle, Xenograft Model Antitumor Assays, Histone Deacetylase Inhibitors, 030104 developmental biology, chemistry, Apoptosis, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Cancer research, Multiple Myeloma, medicine.drug
Abstract

Although having promising anti-myeloma properties, the pan-histone deacetylase inhibitor (HDACi) panobinostat lacks therapeutic activity as a single agent. The aim of the current study was to elucidate the mechanisms underlying multiple myeloma (MM) resistance to panobinostat monotherapy and to define strategies to overcome it. Sensitivity of MM cell lines and primary CD138+ cells from MM patients to panobinostat correlated with reduced expression of the chemokine receptor CXCR4, whereas overexpression of CXCR4 in MM cell lines increased their resistance to panobinostat. Decreased sensitivity to HDACi was associated with reversible G0/G1 cell growth arrest while response was characterized by apoptotic cell death. Analysis of intra-cellular signaling mediators revealed the pro-survival mTOR pathway to be regulated by CXCR4 overexpression. Combining panobinostat with mTOR inhibitor everolimus abrogated the resistance to HDACi and induced synergistic cell death. The combination of panobinostat/everolimus resulted in sustained DNA damage and irreversible suppression of proliferation accompanied by robust apoptosis. Gene expression analysis revealed distinct genetic profiles of single versus combined agent exposure. Whereas panobinostat increased the expression of the cell cycle inhibitor p21, co-treatment with everolimus abrogated the increase in p21 and synergistically downregulated the expression of DNA repair genes and mitotic checkpoint regulators. Importantly, the combination of panobinostat with everolimus effectively targeted CXCR4-expressing resistant MM cells in vivo in the BM niche. In summary, our results uncover the mechanism responsible for the strong synergistic anti-MM activity of dual HDAC and mTOR inhibition and provide the rationale for a novel potential therapeutic approach to treat MM.

Published
2019

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