11 results on '"Zagozdzon A"'
Search Results
2. Serine Biosynthesis Pathway Supports MYC-miR-494-EZH2 Feed-Forward Circuit Necessary to Maintain Metabolic and Epigenetic Reprogramming of Burkitt Lymphoma Cells
- Author
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Agnieszka Łoboda, Aleksandra Grochowska, Agnieszka Sroka-Porada, Agnieszka Graczyk-Jarzynka, Patryk Górniak, Monika Prochorec-Sobieszek, Magdalena Cybulska, Malgorzata Firczuk, Przemyslaw Juszczynski, Bjoern Chapuy, Monika Noyszewska-Kania, Michal Kopczynski, Adam Ząbek, Tomasz Rzymski, Maciej Szydlowski, Piotr Młynarz, Radoslaw Zagozdzon, Anna Polak, Emilia Bialopiotrowicz, Michal Mikula, Ewa Jabłońska, Justyna Martyka, Neli Kachamakova-Trojanowska, Anna Szumera-Ciećkiewicz, Jozef Dulak, Krzysztof Brzózka, Piotr Kowalczyk, and Karolina Pyziak
- Subjects
Cancer Research ,MYC ,lcsh:RC254-282 ,Article ,Serine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Biosynthesis ,Histone methylation ,Transcription factor ,030304 developmental biology ,0303 health sciences ,Oncogene ,Chemistry ,EZH2 ,Burkitt lymphoma ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,3. Good health ,Cell biology ,serine biosynthesis pathway ,Oncology ,KLF4 ,030220 oncology & carcinogenesis ,Histone methyltransferase ,metabolism - Abstract
Burkitt lymphoma (BL) is a rapidly growing tumor, characterized by high anabolic requirements. The MYC oncogene plays a central role in the pathogenesis of this malignancy, controlling genes involved in apoptosis, proliferation, and cellular metabolism. Serine biosynthesis pathway (SBP) couples glycolysis to folate and methionine cycles, supporting biosynthesis of certain amino acids, nucleotides, glutathione, and a methyl group donor, S-adenosylmethionine (SAM). We report that BLs overexpress SBP enzymes, phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1). Both genes are controlled by the MYC-dependent ATF4 transcription factor. Genetic ablation of PHGDH/PSAT1 or chemical PHGDH inhibition with NCT-503 decreased BL cell lines proliferation and clonogenicity. NCT-503 reduced glutathione level, increased reactive oxygen species abundance, and induced apoptosis. Consistent with the role of SAM as a methyl donor, NCT-503 decreased DNA and histone methylation, and led to the re-expression of ID4, KLF4, CDKN2B and TXNIP tumor suppressors. High H3K27me3 level is known to repress the MYC negative regulator miR-494. NCT-503 decreased H3K27me3 abundance, increased the miR-494 level, and reduced the expression of MYC and MYC-dependent histone methyltransferase, EZH2. Surprisingly, chemical/genetic disruption of SBP did not delay BL and breast cancer xenografts growth, suggesting the existence of mechanisms compensating the PHGDH/PSAT1 absence in vivo.
- Published
- 2020
3. Targeting Negative and Positive Immune Checkpoints with Monoclonal Antibodies in Therapy of Cancer
- Author
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Agnieszka Graczyk-Jarzynka, Zofia Pilch, Katsiaryna Marhelava, Radoslaw Zagozdzon, and Malgorzata Bajor
- Subjects
0301 basic medicine ,Cancer Research ,medicine.drug_class ,medicine.medical_treatment ,animal diseases ,chemical and pharmacologic phenomena ,Review ,Monoclonal antibody ,lcsh:RC254-282 ,combination therapy ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cancer immunotherapy ,medicine ,business.industry ,Cancer ,Immunotherapy ,biochemical phenomena, metabolism, and nutrition ,immune checkpoints ,Acquired immune system ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,tumor immunity ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Monoclonal ,Immunology ,Cancer cell ,bacteria ,monoclonal antibodies ,immunotherapy ,business - Abstract
The immune checkpoints are regulatory molecules that maintain immune homeostasis in physiological conditions. By sending T cells a series of co-stimulatory or co-inhibitory signals via receptors, immune checkpoints can both protect healthy tissues from adaptive immune response and activate lymphocytes to remove pathogens effectively. However, due to their mode of action, suppressive immune checkpoints may serve as unwanted protection for cancer cells. To restore the functioning of the immune system and make the patient’s immune cells able to recognize and destroy tumors, monoclonal antibodies are broadly used in cancer immunotherapy to block the suppressive or to stimulate the positive immune checkpoints. In this review, we aim to present the current state of application of monoclonal antibodies in clinics, used either as single agents or in a combined treatment. We discuss the limitations of these therapies and possible problem-solving with combined treatment approaches involving both non-biological and biological agents. We also highlight the most promising strategies based on the use of monoclonal or bispecific antibodies targeted on immune checkpoints other than currently implemented in clinics.
- Published
- 2019
4. Targeting Negative and Positive Immune Checkpoints with Monoclonal Antibodies in Therapy of Cancer
- Author
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Marhelava, Katsiaryna, primary, Pilch, Zofia, additional, Bajor, Malgorzata, additional, Graczyk-Jarzynka, Agnieszka, additional, and Zagozdzon, Radoslaw, additional
- Published
- 2019
- Full Text
- View/download PDF
5. Monoclonal Antibodies in Dermatooncology—State of the Art and Future Perspectives
- Author
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Joanna Domagala, Radoslaw Zagozdzon, Magdalena Winiarska, Malgorzata Bobrowicz, Roberta Vasconcelos-Berg, and Emmanuella Guenova
- Subjects
0301 basic medicine ,Cancer Research ,medicine.drug_class ,medicine.medical_treatment ,Review ,Monoclonal antibody ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Medicine ,business.industry ,Cancer ,Immunotherapy ,immune checkpoints ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,3. Good health ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,Molecular targets ,Rituximab ,immunotherapy ,monoclonal antibodies ,Skin cancer ,dermatooncology ,business ,medicine.drug - Abstract
Monoclonal antibodies (mAbs) targeting specific proteins are currently the most popular form of immunotherapy used in the treatment of cancer and other non-malignant diseases. Since the first approval of anti-CD20 mAb rituximab in 1997 for the treatment of B-cell malignancies, the market is continuously booming and the clinically used mAbs have undergone a remarkable evolution. Novel molecular targets are constantly emerging and the development of genetic engineering have facilitated the introduction of modified mAbs with improved safety and increased capabilities to activate the effector mechanisms of the immune system. Next to their remarkable success in hematooncology, mAbs have also an already established role in the treatment of solid malignancies. The recent development of mAbs targeting the immune checkpoints has opened new avenues for the use of this form of immunotherapy, also in the immune-rich milieu of the skin. In this review we aim at presenting a comprehensive view of mAbs’ application in the modern treatment of skin cancer. We present the characteristics and efficacy of mAbs currently used in dermatooncology and summarize the recent clinical trials in the field. We discuss the side effects and strategies for their managing.
- Published
- 2019
6. Prospects for NK Cell Therapy of Sarcoma
- Author
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Radoslaw Zagozdzon, Mieszko Lachota, Marianna Vincenti, Kjetil Boye, Magdalena Winiarska, and Karl-Johan Malmberg
- Subjects
0301 basic medicine ,Cancer Research ,sarcoma ,cell-mediated cytotoxicity ,medicine.medical_treatment ,Cell ,Review ,lcsh:RC254-282 ,Metastasis ,Cell therapy ,Natural Killer (NK) cells ,03 medical and health sciences ,0302 clinical medicine ,medicine ,cancer ,Neoplasm ,tumor microenvironment (TME) ,chimeric antigen receptor (CAR) ,business.industry ,Innate lymphoid cell ,adoptive cell therapy ,Immunotherapy ,solid tumors ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Immunosurveillance ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,immunotherapy ,Sarcoma ,business - Abstract
Simple Summary Sarcomas are a group of aggressive tumors originating from mesenchymal tissues. Patients with advanced disease have poor prognosis due to the ineffectiveness of current treatment protocols. A subset of lymphocytes called natural killer (NK) cells is capable of effective surveillance and clearance of sarcomas, constituting a promising tool for immunotherapeutic treatment. However, sarcomas can cause impairment in NK cell function, associated with enhanced tumor growth and dissemination. In this review, we discuss the molecular mechanisms of sarcoma-mediated suppression of NK cells and their implications for the design of novel NK cell-based immunotherapies against sarcoma. Abstract Natural killer (NK) cells are innate lymphoid cells with potent antitumor activity. One of the most NK cell cytotoxicity-sensitive tumor types is sarcoma, an aggressive mesenchyme-derived neoplasm. While a combination of radical surgery and radio- and chemotherapy can successfully control local disease, patients with advanced sarcomas remain refractory to current treatment regimens, calling for novel therapeutic strategies. There is accumulating evidence for NK cell-mediated immunosurveillance of sarcoma cells during all stages of the disease, highlighting the potential of using NK cells as a therapeutic tool. However, sarcomas display multiple immunoevasion mechanisms that can suppress NK cell function leading to an uncontrolled tumor outgrowth. Here, we review the current evidence for NK cells’ role in immune surveillance of sarcoma during disease initiation, promotion, progression, and metastasis, as well as the molecular mechanisms behind sarcoma-mediated NK cell suppression. Further, we apply this basic understanding of NK–sarcoma crosstalk in order to identify and summarize the most promising candidates for NK cell-based sarcoma immunotherapy.
- Published
- 2020
7. Monoclonal Antibodies in Dermatooncology—State of the Art and Future Perspectives
- Author
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Bobrowicz, Malgorzata, primary, Zagozdzon, Radoslaw, additional, Domagala, Joanna, additional, Vasconcelos-Berg, Roberta, additional, Guenova, Emmanuella, additional, and Winiarska, Magdalena, additional
- Published
- 2019
- Full Text
- View/download PDF
8. Hydrogen-Peroxide Synthesis and LDL-Uptake Controls Immunosuppressive Properties in Monocyte-Derived Dendritic Cells.
- Author
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Menzner, Ann-Katrin, Rottmar, Tanja, Voelkl, Simon, Bosch, Jacobus J., Mougiakakos, Dimitrios, Mackensen, Andreas, Resheq, Yazid J., Winiarska, Magdalena, Firczuk, Malgorzata, and Zagozdzon, Radoslaw
- Subjects
REACTIVE oxygen species ,CATALASE ,CELL differentiation ,DENDRITIC cells ,HYDROGEN peroxide ,IMMUNOSUPPRESSION ,LIVER tumors ,LOW density lipoproteins ,MONOCYTES ,PHAGOCYTOSIS ,PHENOTYPES ,ACUTE myeloid leukemia - Abstract
Simple Summary: Given the encouraging success of immunotherapy in cancer, the role of metabolism in tumor immune-evasion is an emerging research field with a unique potential to overcome current limitations in immunotherapy. Herein, hepatic stromal cells, which may act as immunological bystanders in cancer, are capable of inducing immunosuppressive phenotypes in monocytic cells by controlling hydrogen peroxide (H
2 O2 -) metabolism. As monocytic cells play an important role in tumor-immunology, we sought to identify the underlying mechanisms. Herein, we unraveled a complex interaction between cholesterol/LDL- and H2 O2 -metabolism: Extracellular depletion of H2 O2 leads to enhanced H2 O2 -production with a consecutive increase in LDL-uptake throughout differentiation of monocytes to monocyte-derived dendritic cells and, as a result, to the induction of distinct immunosuppressive properties. These findings shed new light on the role of LDL-metabolism in tumor-immunology and might help to further improve immunotherapeutic approaches against cancer. Background and Aims: Induction of myeloid-derived suppressor cells (MDSC) is a critical step in immune cell evasion by different cancer types, including liver cancer. In the liver, hepatic stromal cells orchestrate induction of MDSCs, employing a mechanism dependent on hydrogen peroxide (H2 O2 ) depletion. However, the effects on monocyte-derived dendritic cells (moDCs) are unknown. Methods: Monocytes from healthy donors were differentiated to moDCs in the presence of extracellular enzymatic H2 O2 -depletion (hereinafter CAT-DCs), and studied phenotypically and functionally. To elucidate the underlying molecular mechanisms, we analyzed H2 O2 - and LDL-metabolism as they are interconnected in monocyte-driven phagocytosis. Results: CAT-DCs were of an immature DC phenotype, particularly characterized by impaired expression of the costimulatory molecules CD80/86. Moreover, CAT-DCs were able to suppress T-cells using indoleamine 2,3-dioxygenase (IDO), and induced IL10/IL17-secreting T-cells—a subtype reported to exert immunosuppression in acute myeloid leukemia. CAT-DCs also displayed significantly increased NADPH-oxidase-driven H2 O2 -production, enhancing low-density lipoprotein (LDL)-uptake. Blocking LDL-uptake restored maturation, and attenuated the immunosuppressive properties of CAT-DCs. Discussion: Here, we report a novel axis between H2 O2 - and LDL-metabolism controlling tolerogenic properties in moDCs. Given that moDCs are pivotal in tumor-rejection, and lipid-accumulation is associated with tumor-immune-escape, LDL-metabolism appears to play an important role in tumor-immunology. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
9. Immune Evasion as the Main Challenge for Immunotherapy of Cancer
- Author
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Radoslaw Zagozdzon, Magdalena Winiarska, and Malgorzata Firczuk
- Subjects
n/a ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Immune evasion is currently considered one of the most prominent hallmarks of cancer [...]
- Published
- 2022
- Full Text
- View/download PDF
10. Targeting Negative and Positive Immune Checkpoints with Monoclonal Antibodies in Therapy of Cancer
- Author
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Katsiaryna Marhelava, Zofia Pilch, Malgorzata Bajor, Agnieszka Graczyk-Jarzynka, and Radoslaw Zagozdzon
- Subjects
immune checkpoints ,monoclonal antibodies ,immunotherapy ,tumor immunity ,combination therapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The immune checkpoints are regulatory molecules that maintain immune homeostasis in physiological conditions. By sending T cells a series of co-stimulatory or co-inhibitory signals via receptors, immune checkpoints can both protect healthy tissues from adaptive immune response and activate lymphocytes to remove pathogens effectively. However, due to their mode of action, suppressive immune checkpoints may serve as unwanted protection for cancer cells. To restore the functioning of the immune system and make the patient’s immune cells able to recognize and destroy tumors, monoclonal antibodies are broadly used in cancer immunotherapy to block the suppressive or to stimulate the positive immune checkpoints. In this review, we aim to present the current state of application of monoclonal antibodies in clinics, used either as single agents or in a combined treatment. We discuss the limitations of these therapies and possible problem-solving with combined treatment approaches involving both non-biological and biological agents. We also highlight the most promising strategies based on the use of monoclonal or bispecific antibodies targeted on immune checkpoints other than currently implemented in clinics.
- Published
- 2019
- Full Text
- View/download PDF
11. Monoclonal Antibodies in Dermatooncology—State of the Art and Future Perspectives
- Author
-
Malgorzata Bobrowicz, Radoslaw Zagozdzon, Joanna Domagala, Roberta Vasconcelos-Berg, Emmanuella Guenova, and Magdalena Winiarska
- Subjects
dermatooncology ,immune checkpoints ,immunotherapy ,monoclonal antibodies ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Monoclonal antibodies (mAbs) targeting specific proteins are currently the most popular form of immunotherapy used in the treatment of cancer and other non-malignant diseases. Since the first approval of anti-CD20 mAb rituximab in 1997 for the treatment of B-cell malignancies, the market is continuously booming and the clinically used mAbs have undergone a remarkable evolution. Novel molecular targets are constantly emerging and the development of genetic engineering have facilitated the introduction of modified mAbs with improved safety and increased capabilities to activate the effector mechanisms of the immune system. Next to their remarkable success in hematooncology, mAbs have also an already established role in the treatment of solid malignancies. The recent development of mAbs targeting the immune checkpoints has opened new avenues for the use of this form of immunotherapy, also in the immune-rich milieu of the skin. In this review we aim at presenting a comprehensive view of mAbs’ application in the modern treatment of skin cancer. We present the characteristics and efficacy of mAbs currently used in dermatooncology and summarize the recent clinical trials in the field. We discuss the side effects and strategies for their managing.
- Published
- 2019
- Full Text
- View/download PDF
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