Dr Winiarska Team
Magdalena Winiarska, Phd |
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| Research | Monoclonal antibodies projects: For years our team has aimed at elucidating the molecular mechanisms of the regulation of CD20 antigen and identification of novel therapeutic strategies increasing the efficacy of anti-CD20 monoclonal antibodies (mAbs). In the recent years we have identified numerous molecular pathways determining the efficacy of anti-CD20 immunotherapy (Pyrzynska et al. 2018, Bobrowicz et al. 2017, Bojarczuk et al. 2014, Dwojak et al. 2015, Winiarska et al. 2012 and 2014). Anti-CD20 mAbs have greatly improved the outcome of patients with B-cell malignancies, such as non- Hodgkin’s lymphomas (NHL) and chronic lymphocytic leukemia (CLL). The antitumor action of these antibodies results from triggering effector mechanisms of the immune response leading to the elimination of tumor cells (Fig. 1). The therapy is well tolerated with minor side effects. Anti-CD20 mAbs are successfully incorporated into multidrug regimens. However, their use in monotherapy they rarely results in complete remissions. Therefore, attempts to increase the efficacy of these agents by combining them with other novel anticancer drugs have been proposed for years now. Moreover, up to 50% of the patients treated with anti-CD20 mAbs develops resistance to treatment. One of the mechanisms of this phenomenon is a decreased expression of CD20 antigen on the cell surface. The amount of CD20 in the cell membrane is tightly regulated on diverse levels – transcription, mRNA translation and posttranslational modifications. Moreover, CD20 expression has been shown to be regulated epigenetically e.g. by histone deacetylases (HDAC). Our team has identified a novel hitherto unknown mechanism of regulation of CD20 expression by selective HDAC6 inhibition. We have demonstrated that both specific HDAC6 inhibition as well as HDAC6 silencing using shRNA in tumor cells leads to their substantial sensitization to anti-CD20 mAbs. Currently, in cooperation with Dr Emmanuella Guenova from the Dermatology Clinic in University Hospital Zurich we investigate the role of HDAC6 in the biology of cutaneous T-cell lymphoma (CTCL). Although the role of HDAC6 in the pathogenesis of CTCL has not been sufficiently elucidated, the results of clinical trials suggest that HDAC6 inhibition may decrease clinical symptoms in CTCL patients. In our common project we have investigated the therapeutic potential of selective HDAC6 inhibitors in combination with PI3K inhibitors, a new class of drugs currently tested in clinical trials in CTCL. These agents are characterized with high specificity towards tumor cells and a good safety profile. CAR modifications Our team has also recently begun exploring one of the major breakthroughs in the field of immunotherapy – the use of CARs (chimeric antigen receptors)-modified effector cells in anti-tumor therapies. CARs are synthetic constructs that upon introduction into recipient T cells or NK cells can re-program cytotoxic cells to recognize antigens present on tumor cells. This re-targeting is feasible due to the unique modular CAR construction. CAR receptors consist of an extracellular antibody derived domain (scFv) that is responsible for antigen recognition, intracellular activating domains derived from T cell receptor, and different co-stimulatory domains. CAR receptors literally translate the ability of the antibodies to recognize cognate antigen into stimulating signal resulting in activation of T or NK cells, their concomitant degranulation and cytotoxic effector function. In our research, we actively search for solutions that would benefit CAR-T therapy of solid tumors that up to date does not recapitulate the spectacular success of CAR-T therapy in hematological malignancies. Moreover, we want to elucidate how the CAR re-wired circuits influence the biology and cytotoxicity of T cells and NK cells. In collaboration with prof. Karl-Johan Malmberg from Oslo University Hospital we investigated how education and differentiation status of NK cells influence the CAR re-directed cytotoxicity of NK cells. In our research addressing the solid tumors CAR-based immunotherapy, we focus mainly on developing a modified CAR approach that limits the “on target/off tumor” antigen recognition, as well as minimizes the inhibitory effect of the tumor microenvironment. Our team specifically aims to address these issues by creating CARs that 1) are specifically expressed and activated in the tumor microenvironment, 2) re-wire the biology of CAR-modified cells to resist to the inhibitory signals derived from tumor microenvironment 3) attack the tumor microenvironment residing cells. |
PI | Dr hab. Magdalena Winiarska
Visiting Researcher
Membership
Editorships & Reviewing boards
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| Team members | Postdoctoral Fellows Malgorzata Bobrowicz, PhD
Agnieszka Graczyk-Jarzynka, PhD
Zofia Pilch, PhD
Marta Kłopotowska, PhD
PhD Students Michał Dwojak, MD
Joanna Domagała, Msc
Karolina Soroczyńska, Msc Technicians Iwona Baranowska
Students
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| Research projects |
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| Research papers | 2019 Bojarczuk K, Wienand K, Ryan JA, Chen L, Villalobos-Ortiz M, Mandato E, Stachura J, Letai A, Lawton LN, Chapuy B, Shipp MA. Targeted inhibition of PI3Kα/δ is synergistic with BCL-2 blockade in genetically defined subtypes of DLBCL. Blood. 2019 Jan 3. doi: 10.1182/blood-2018-08-872465. Sasi BK, Martines C, Xerxa E, Porro F, Kalkan H, Fazio R, Turkalj S, Bojnik E, Pyrzynska B, Stachura J, Zerrouqi A, Bobrowicz M, Winiarska M, Priebe V, Bertoni F, Mansouri L, Rosenquist R, Efremov DG. Inhibition of SYK or BTK augments venetoclax sensitivity in SHP1-negative/BCL-2-positive diffuse large B-cell lymphoma. Leukemia. 2019 Mar 14. doi: 10.1038/s41375-019-0442-8. Fidyt K, Pastorczak A, Goral A, Szczygiel K, Fendler W, Muchowicz A, Bartlomiejczyk MA, Madzio J, Cyran J, Graczyk-Jarzynka A, Jansen E, Patkowska E, Lech-Maranda E, Pal D, Blair H, Burdzinska A, Pedzisz P, Glodkowska-Mrowka E, Demkow U, Gawle-Krawczyk K, Matysiak M, Winiarska M, Juszczynski P, Mlynarski W, Heidenreich O, Golab J, Firczuk M. Targeting the thioredoxin system as a novel strategy against B-cell acute lymphoblastic leukemia. Mol Oncol. 2019 May;13(5):1180-1195. doi: 10.1002/1878-0261.12476. Epub 2019 Apr 5. Wolosz D, Walczak A, Szparecki G, Dwojak M, Winiarska M, Wolinska E, Gornicka B. Deleted in Liver Cancer 2 (DLC2) protein expression in hepatocellular carcinoma. Eur J Histochem. 2019 Feb 18;63(1). doi: 10.4081/ejh.2019.2981. Graczyk-Jarzynka A, Goral A, Muchowicz A, Zagozdzon R, Winiarska M, Bajor M, Trzeciecka A, Fidyt K, Krupka JA, Cyran J, Szczygiel K, Efremov DG, Gobessi S, Jagielski A, Siudakowska K, Bobrowicz M, Klopotowska M, Barankiewicz J, Malenda A, Lech-Maranda E, Miazek-Zapala N, Skarzynski PH, Domagala A, Golab J, Firczuk M. Inhibition of thioredoxin-dependent H2O2 removal sensitizes malignant B-cells to pharmacological ascorbate. Redox Biol. 2019 Feb;21:101062. doi: 10.1016/j.redox.2018.11.020. Epub 2018 Nov 29. Anzengruber F, Ignatova D, Schlaepfer T, Chang YT, French LE, Pascolo S, Contassot E, Bobrowicz M, Hoetzenecker W, Guenova E. Divergent LAG-3 versus BTLA, TIGIT, and FCRL3 expression in Sezary syndrome. Leuk Lymphoma. 2019 Jan 14:1-9. doi: 10.1080/10428194.2018.1564827.
2018 Pyrzynska B, Dwojak M, Zerrouqi A, Morlino G, Zapala P, Miazek N, Zagozdzon A, Bojarczuk K, Bobrowicz M, Siernicka M, Machnicki MM, Gobessi S, Barankiewicz J, Lech-Maranda E, Efremov DG, Juszczynski P, Calado D, Golab J, Winiarska M. FOXO1 promotes resistance of non-Hodgkin lymphomas to anti-CD20-based therapy. Oncoimmunology. 2018 Jan 25;7(5):e1423183. doi: 10.1080/2162402X.2017.1423183. eCollection 2018. Oei VYS, Siernicka M, Graczyk-Jarzynka A, Hoel HJ, Yang W, Palacios D, Almåsbak H, Bajor M, Clement D, Brandt L, Önfelt B, Goodridge J, Winiarska M, Zagozdzon R, Olweus J, Kyte JA, Malmberg KJ. Intrinsic Functional Potential of NK-Cell Subsets Constrains Retargeting Driven by Chimeric Antigen Receptors. Cancer Immunol Res. 2018 Apr;6(4):467-480. doi: 10.1158/2326-6066.CIR-17-0207. Epub 2018 Feb 19. Domagala A, Fidyt K, Bobrowicz M, Stachura J, Szczygiel K, Firczuk M. Typical and Atypical Inducers of Lysosomal Cell Death: A Promising Anticancer Strategy. Int J Mol Sci. 2018 Aug, 1;19(8). pii: E2256. doi: 10.3390/ijms19082256. Domagala A, Stachura J, Gabrysiak M, Muchowicz A, Zagozdzon R, Golab J, Firczuk M. Inhibition of autophagy sensitizes cancer cells to Photofrin-based photodynamic therapy. BMC Cancer. 2018 Feb 20. doi: 10.1186/s12885-018-4126-y. Bajor M, Zych AO, Graczyk-Jarzynka A, Muchowicz A, Firczuk M, Trzeciak L, Gaj P, Domagala A, Siernicka M, Zagozdzon A, Siedlecki P, Kniotek M, O'Leary PC, Golab J, Zagozdzon R. Targeting peroxiredoxin 1 impairs growth of breast cancer cells and potently sensitises these cells to prooxidant agents. Br J Cancer. 2018 Oct;119(7):873-884. doi: 10.1038/s41416-018-0263-y. Epub 2018 Oct 5. Burdzinska A, Dybowski B, Zarychta-Wiśniewska W, Kulesza A, Butrym M, Zagozdzon R, Graczyk-Jarzynka A, Radziszewski P, Gajewski Z, Paczek L. Intraurethral co-transplantation of bone marrow mesenchymal stem cells and muscle-derived cells improves the urethral closure. Stem Cell Res Ther. 2018 Sep 21;9(1):239. doi: 10.1186/s13287-018-0990-2. Burdzinska A, Dybowski B, Zarychta-Wiśniewska W, Kulesza A, Hawryluk J, Graczyk-Jarzynka A, Kaupa P, Gajewski Z, Paczek L. Limited accuracy of transurethral and periurethral intrasphincteric injections of cellular suspension. Neurourol Urodyn. 2018 Jun;37(5):1612-1622. doi: 10.1002/nau.23522. Epub 2018 Feb 27. Chlebowska-Tuz J, Sokolowska O, Gaj P, Lazniewski M, Firczuk M, Borowiec K, Sas-Nowosielska H, Bajor M, Malinowska A, Muchowicz A, Ramji K, Golab J, Nowis D, et al. (2018) Inhibition of protein disulfide isomerase induces differentiation of acute myeloid leukemia cells Haematologica doi:10.3324/haematol.2018.190231
2017 Winiarska M, Nowis D, Firczuk M, Zagozdzon A, Gabrysiak M, Sadowski R, Barankiewicz J, Dwojak M, Golab J. Selection of an optimal promoter for gene transfer in normal B cells. Mol Med Rep. 2017 Sep;16(3):3041-3048. doi: 10.3892/mmr.2017.6974. Epub 2017 Jul 14. Bobrowicz M, Dwojak M, Pyrzynska B, Stachura J, Muchowicz A, Berthel E, Dalla Venezia N, Kozikowski M, Siernicka M, Miazek N, Zapala P, Domagala A, Bojarczuk K, Malenda A, Barankiewicz J, Graczyk-Jarzynka A, Zagozdzon A, Gabrysiak M, Diaz JJ, Karp M, Lech-Maranda E, Firczuk M, Giannopoulos K, Efremov DG, Laurenti L, Baatout D, Frenzel L, Malinowska A, Slabicki M, Zenz T, Zerrouqi A, Golab J, Winiarska M. “HDAC6 inhibition up-regulates CD20 levels and increases the efficacy of anti-CD20 monoclonal antibodies” Blood. 2017 Oct 5;130(14):1628-1638. Muchowicz A, Wachowska M, Stachura J, Tonecka K, Gabrysiak M, Wołosz D, Pilch Z, Kilarski WW, Boon L, Klaus TJ, Golab J. Inhibition of lymphangiogenesis impairs antitumour effects of photodynamic therapy and checkpoint inhibitors in mice. European Journal of Cancer. 2017 Sep. doi: 10.1016/j.ejca.2017.06.004. Graczyk-Jarzynka A, Zagozdzon R, Muchowicz A, Siernicka M, Juszczynski P, Firczuk M New insights into redox homeostasis as a therapeutic target in B-cell malignancies. Curr Opin Hematol. 2017 Jul;24(4):393-401. doi: 10.1097/MOH.0000000000000351. Review.
2016 Słabicki M, Lee KS, Jethwa A, Sellner L, Sacco F, Walther T, Hüllein J, Dietrich S, Wu B, Lipka DB, Oakes CC, Mamidi S, Pyrzyńska B, Winiarska M, Oleś M, Seifert M, Plass C, Kirschfink M, Boettcher M, Gołąb J, Huber W, Fröhling S, Zenz T. Dissection of CD20 regulation in lymphoma using RNAi. Leukemia. 2016 Dec;30(12):2409-2412. Gabrysiak M, Wachowska M, Barankiewicz J, Pilch Z, Ratajska A, Skrzypek E, Winiarska M, Domagala A, Rygiel TP, Jozkowicz A, Boon L, Golab J, Firczuk M. Low dose of GRP78-targeting subtilase cytotoxin improves the efficacy of photodynamic therapy in vivo. Oncol Rep. 2016 Jun;35(6):3151-8. doi: 10.3892/or.2016.4723 Stachura J, Wachowska M, Kilarski W, Güç E, Golab J, Muchowicz A. The dual role of tumor lymphatic vessels in dissemination of metastases and immune response development. Oncoimmunology. 2016 May 13. doi: 10.1080/2162402X.2016.1182278.
2015 Trzeciecka A, Klossowski S, Bajor M, Zagozdzon R, Gaj P, Muchowicz A, Malinowska A, Czerwoniec A, Barankiewicz J, Domagala A, Chlebowska J, Prochorec-Sobieszek M, Winiarska M, Ostaszewski R, Gwizdalska I, Golab J, Nowis D, Firczuk M. Dimeric peroxiredoxins are druggable targets in human Burkitt lymphoma. Oncotarget. 2015 Nov 30. doi: 10.18632/oncotarget.6435. Siernicka M, Winiarska M, Bajor M, Firczuk M, Muchowicz A, Bobrowicz M, Fauriat C, Golab J, Olive D, Zagozdzon R. “Adenanthin, a new inhibitor of thiol-dependent antioxidant enzymes, impairs the effector functions of human natural killer cells” Immunology. 2015 Sep;146(1):173-83. Dwojak M, Bobrowicz M, Bil J, Bojarczuk K, Pyrzynska B, Siernicka M, Malenda A, Lech-Maranda E, Tomczak W, Giannopoulos K, Golab J, Winiarska M. “Sorafenib improves rituximab and ofatumumab efficacy by decreasing the expression of complement regulating proteins” Blood Cancer J. 2015 Apr 10;5:e300 Dudek-Peric AM, Ferreira GB, Muchowicz A, Wouters J, Prada N, Matrin S, Kiviluoto S, Winiarska M, Boon L, Mathieu C, van den Oord J, Stas M, Gougeon ML, Golab J, Garg AD, Agostinis P. ”Anti-tumor immunity triggered by melphalan is potentiated by melanoma cell surface associated calreticulin” Cancer Res. 2015 Mar 11. pii: canres.2089.2014.
2014 Winiarska M, Bojarczuk K, Pyrzynska B, Bil J, Siernicka M, Dwojak M, Bobrowicz M, Miazek N, Zapala P, Zagozdzon A, Krol M, Syta A, Podszywalow-Bartnicka P, Pilch Z, Dabrowska-Iwanicka A, Juszczynski P, Efremov DG, Slabicki M, Zenz T, Le Roy A, Olive D, Rygiel TP, Leusen JH, Golab J. “Inhibitors of SRC kinases impair antitumor activity of anti-CD20 monoclonal antibodies” mAbs 6:5, 1–13; September/October 2014 Bojarczuk K, Siernicka M, Dwojak M, Bobrowicz M, Pyrzynska B, Gaj P, Karp M, Giannopoulos K, Efremov DG, Fauriat C, Golab J and Winiarska M. “B-cell receptor pathway inhibitors affect CD20 levels and impair antitumor activity of anti-CD20 monoclonal antibodies” Leukemia. 2014 May;28(5):1163-7 Muchowicz A, Firczuk M, Chlebowska J, Nowis D, Stachura J, Barankiewicz J, Trzeciecka A, Kłossowski S, Ostaszewski R, Zagożdżon R, Pu JX, Sun HD, Golab J. Adenanthin targets proteins involved in the regulation of disulphide bonds. Biochemical pharmacology. 2014 May 15. doi: 10.1016/j.bcp.2014.02.022. |
