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Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Review Article

Signal Pathways and Therapeutic Prospects of Diffuse Large B Cell Lymphoma

Author(s): Feifei Sun, Xiaosheng Fang* and Xin Wang*

Volume 19, Issue 17, 2019

Page: [2047 - 2059] Pages: 13

DOI: 10.2174/1871520619666190925143216

Price: $65

Abstract

Background: Diffuse Large B Cell Lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma which is heterogeneous both clinically and morphologically. Over the past decades, significant advances have been made in the understanding of the molecular genesis, leading to the identification of multiple pathways and molecules that can be targeted for clinical benefit.

Objective: The current review aims to present a brief overview of signal pathways of DLBCL, which mainly focus on B-cell antigen Receptor (BCR), Nuclear Factor-κB (NF-κB), Phosphatidylinositol-3-Kinase (PI3K) – protein kinase B (Akt) – mammalian Target of Rapamycin (mTOR), Janus Kinase (JAK) – Signal Transducer and Activator (STAT), Wnt/β-catenin, and P53 pathways.

Methods: Activation of signal pathways may contribute to the generation, development, chemotherapy sensitivity of DLBCL, and expression of pathway molecules is associated with the prognosis of DLBCL. Some agents targeting these pathways have been proved effective and relevant clinical trials are in progress. These agents used single or combined with chemotherapy/each other might raise the possibility of improving clinical outcomes in DLBCL.

Conclusion: This review presents several signal pathways of DLBCL and targeted agents had a tendency to improve the curative effect, especially in high-risk or relapsed/refractory DLBCL.

Keywords: Diffuse large B-cell lymphoma, B-cell antigen receptor, nuclear factor-κB, phosphatidylinositol-3-kinase, Janus kinase, Wnt/β- catenin, P53 pathway.

Graphical Abstract

[1]
A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. The Non-Hodgkin’s Lymphoma Classification Project. Blood, 1997, 89(11), 3909-3918.
[PMID: 9166827]
[2]
Hans, C.P.; Weisenburger, D.D.; Greiner, T.C.; Gascoyne, R.D.; Delabie, J.; Ott, G.; Müller-Hermelink, H.K.; Campo, E.; Braziel, R.M.; Jaffe, E.S.; Pan, Z.; Farinha, P.; Smith, L.M.; Falini, B.; Banham, A.H.; Rosenwald, A.; Staudt, L.M.; Connors, J.M.; Armitage, J.O.; Chan, W.C. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood, 2004, 103(1), 275-282.
[http://dx.doi.org/10.1182/blood-2003-05-1545] [PMID: 14504078]
[3]
Rosenwald, A.; Wright, G.; Chan, W.C.; Connors, J.M.; Campo, E.; Fisher, R.I.; Gascoyne, R.D.; Muller-Hermelink, H.K.; Smeland, E.B.; Giltnane, J.M.; Hurt, E.M.; Zhao, H.; Averett, L.; Yang, L.; Wilson, W.H.; Jaffe, E.S.; Simon, R.; Klausner, R.D.; Powell, J.; Duffey, P.L.; Longo, D.L.; Greiner, T.C.; Weisenburger, D.D.; Sanger, W.G.; Dave, B.J.; Lynch, J.C.; Vose, J.; Armitage, J.O.; Montserrat, E.; López-Guillermo, A.; Grogan, T.M.; Miller, T.P.; LeBlanc, M.; Ott, G.; Kvaloy, S.; Delabie, J.; Holte, H.; Krajci, P.; Stokke, T.; Staudt, L.M. Lymphoma/Leukemia Molecular Profiling Project. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N. Engl. J. Med., 2002, 346(25), 1937-1947.
[http://dx.doi.org/10.1056/NEJMoa012914] [PMID: 12075054]
[4]
Lu, T.X.; Miao, Y.; Wu, J.Z.; Gong, Q.X.; Liang, J.H.; Wang, Z.; Wang, L.; Fan, L.; Hua, D.; Chen, Y.Y.; Xu, W.; Zhang, Z.H.; Li, J.Y. The distinct clinical features and prognosis of the CD10+MUM1+ and CD10Bcl6MUM1 diffuse large B-cell lymphoma. Sci. Rep., 2016, 6, 20465.
[http://dx.doi.org/10.1038/srep20465] [PMID: 26857366]
[5]
Epperla, N.; Maddocks, K.J.; Salhab, M.; Chavez, J.C.; Reddy, N.; Karmali, R.; Umyarova, E.; Bachanova, V.; Costa, C.; Glenn, M.; Calzada, O.; Xavier, A.C.; Zhou, Z.; Hossain, N.M.; Hernandez-Ilizaliturri, F.J.; Al-Mansour, Z.; Barta, S.K.; Chhabra, S.; Lansigan, F.; Mehta, A.; Jaglal, M.V.; Evens, A.M.; Flowers, C.R.; Cohen, J.B.; Fenske, T.S.; Hamadani, M.; Costa, L.J. C-MYC-positive relapsed and refractory, diffuse large B-cell lymphoma: Impact of additional “hits” and outcomes with subsequent therapy. Cancer, 2017, 123(22), 4411-4418.
[http://dx.doi.org/10.1002/cncr.30895] [PMID: 28749548]
[6]
Friess, M.D.; Pluhackova, K.; Böckmann, R.A. Structural model of the mIgM B-cell receptor transmembrane domain from self-association molecular dynamics simulations. Front. Immunol., 2018, 9, 2947 Published 2018 Dec 17.
[http://dx.doi.org/10.3389/fimmu.2018.02947]
[7]
Maity, P.C.; Datta, M.; Nicolò, A.; Jumaa, H. Isotype specific assembly of B Cell antigen receptors and synergism with chemokine receptor CXCR4. Front. Immunol., 2018, 9, 2988.
[http://dx.doi.org/10.3389/fimmu.2018.02988.]
[8]
Myklebust, J.H.; Brody, J.; Kohrt, H.E.; Kolstad, A.; Czerwinski, D.K.; Wälchli, S.; Green, M.R.; Trøen, G.; Liestøl, K.; Beiske, K.; Houot, R.; Delabie, J.; Alizadeh, A.A.; Irish, J.M.; Levy, R. Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling. Blood, 2017, 129(6), 759-770.
[http://dx.doi.org/10.1182/blood-2016-05-718494] [PMID: 28011673]
[9]
Yasuhiro, T.; Sawada, W.; Klein, C.; Kozaki, R.; Hotta, S.; Yoshizawa, T. Anti-tumor efficacy study of the Bruton’s tyrosine kinase (BTK) inhibitor, ONO/GS-4059, in combination with the glycoengineered type II anti-CD20 monoclonal antibody obinutuzumab (GA101) demonstrates superior in vivo efficacy compared to ONO/GS-4059 in combination with rituximab. Leuk. Lymphoma, 2017, 58(3), 699-707.
[http://dx.doi.org/10.1080/10428194.2016.1201567] [PMID: 27684575]
[10]
Yang, Y.; Kelly, P.; Shaffer, A.L., III; Schmitz, R.; Yoo, H.M.; Liu, X.; Huang, D.W.; Webster, D.; Young, R.M.; Nakagawa, M.; Ceribelli, M.; Wright, G.W.; Yang, Y.; Zhao, H.; Yu, X.; Xu, W.; Chan, W.C.; Jaffe, E.S.; Gascoyne, R.D.; Campo, E.; Rosenwald, A.; Ott, G.; Delabie, J.; Rimsza, L.; Staudt, L.M. Targeting non-proteolytic protein ubiquitination for the treatment of diffuse large B Cell Lymphoma. Cancer Cell, 2016, 29(4), 494-507.
[http://dx.doi.org/10.1016/j.ccell.2016.03.006] [PMID: 27070702]
[11]
Szydlowski, M.; Kiliszek, P.; Sewastianik, T.; Jablonska, E.; Bialopiotrowicz, E.; Gorniak, P.; Polak, A.; Markowicz, S.; Nowak, E.; Grygorowicz, M.A.; Prochorec-Sobieszek, M.; Szumera-Cieckiewicz, A.; Malenda, A.; Lech-Maranda, E.; Warzocha, K.; Juszczynski, P. FOXO1 activation is an effector of SYK and AKT inhibition in tonic BCR signal-dependent diffuse large B-cell lymphomas. Blood, 2016, 127(6), 739-748.
[http://dx.doi.org/10.1182/blood-2015-06-654111] [PMID: 26585955]
[12]
Wilson, W.H.; Young, R.M.; Schmitz, R.; Yang, Y.; Pittaluga, S.; Wright, G.; Lih, C.J.; Williams, P.M.; Shaffer, A.L.; Gerecitano, J.; de Vos, S.; Goy, A.; Kenkre, V.P.; Barr, P.M.; Blum, K.A.; Shustov, A.; Advani, R.; Fowler, N.H.; Vose, J.M.; Elstrom, R.L.; Habermann, T.M.; Barrientos, J.C.; McGreivy, J.; Fardis, M.; Chang, B.Y.; Clow, F.; Munneke, B.; Moussa, D.; Beaupre, D.M.; Staudt, L.M. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat. Med., 2015, 21(8), 922-926.
[http://dx.doi.org/10.1038/nm.3884] [PMID: 26193343]
[13]
Havranek, O.; Xu, J.; Köhrer, S.; Wang, Z.; Becker, L.; Comer, J.M.; Henderson, J.; Ma, W.; Man Chun Ma, J.; Westin, J.R.; Ghosh, D.; Shinners, N.; Sun, L.; Yi, A.F.; Karri, A.R.; Burger, J.A.; Zal, T.; Davis, R.E. Tonic B-cell receptor signaling in diffuse large B-cell lymphoma. Blood, 2017, 130(8), 995-1006.
[http://dx.doi.org/10.1182/blood-2016-10-747303] [PMID: 28646116]
[14]
Takahashi, K.; Sivina, M.; Hoellenriegel, J.; Oki, Y.; Hagemeister, F.B.; Fayad, L.; Romaguera, J.E.; Fowler, N.; Fanale, M.A.; Kwak, L.W.; Samaniego, F.; Neelapu, S.; Xiao, L.; Huang, X.; Kantarjian, H.; Keating, M.J.; Wierda, W.; Fu, K.; Chan, W.C.; Vose, J.M.; O’Brien, S.; Davis, R.E.; Burger, J.A. CCL3 and CCL4 are biomarkers for B cell receptor pathway activation and prognostic serum markers in diffuse large B cell lymphoma. Br. J. Haematol., 2015, 171(5), 726-735.
[http://dx.doi.org/10.1111/bjh.13659] [PMID: 26358140]
[15]
Davis, R.E.; Ngo, V.N.; Lenz, G.; Tolar, P.; Young, R.M.; Romesser, P.B.; Kohlhammer, H.; Lamy, L.; Zhao, H.; Yang, Y.; Xu, W.; Shaffer, A.L.; Wright, G.; Xiao, W.; Powell, J.; Jiang, J.K.; Thomas, C.J.; Rosenwald, A.; Ott, G.; Muller-Hermelink, H.K.; Gascoyne, R.D.; Connors, J.M.; Johnson, N.A.; Rimsza, L.M.; Campo, E.; Jaffe, E.S.; Wilson, W.H.; Delabie, J.; Smeland, E.B.; Fisher, R.I.; Braziel, R.M.; Tubbs, R.R.; Cook, J.R.; Weisenburger, D.D.; Chan, W.C.; Pierce, S.K.; Staudt, L.M. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature, 2010, 463(7277), 88-92.
[http://dx.doi.org/10.1038/nature08638] [PMID: 20054396]
[16]
Goldstein, R.L.; Yang, S.N.; Taldone, T.; Chang, B.; Gerecitano, J.; Elenitoba-Johnson, K.; Shaknovich, R.; Tam, W.; Leonard, J.P.; Chiosis, G.; Cerchietti, L.; Melnick, A. Pharmacoproteomics identifies combinatorial therapy targets for diffuse large B cell lymphoma. J. Clin. Invest., 2015, 125(12), 4559-4571.
[http://dx.doi.org/10.1172/JCI80714] [PMID: 26529251]
[17]
Dunleavy, K.; Erdmann, T.; Lenz, G. Targeting the B-cell receptor pathway in diffuse large B-cell lymphoma. Cancer Treat. Rev., 2018, 65, 41-46.
[http://dx.doi.org/10.1016/j.ctrv.2018.01.002] [PMID: 29549872]
[18]
Friedberg, J.W.; Sharman, J.; Sweetenham, J.; Johnston, P.B.; Vose, J.M.; Lacasce, A.; Schaefer-Cutillo, J.; De Vos, S.; Sinha, R.; Leonard, J.P.; Cripe, L.D.; Gregory, S.A.; Sterba, M.P.; Lowe, A.M.; Levy, R.; Shipp, M.A. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood, 2010, 115(13), 2578-2585.
[http://dx.doi.org/10.1182/blood-2009-08-236471] [PMID: 19965662]
[19]
Flinn, I.W.; Bartlett, N.L.; Blum, K.A.; Ardeshna, K.M.; LaCasce, A.S.; Flowers, C.R.; Shustov, A.R.; Thress, K.S.; Mitchell, P.; Zheng, F.; Skolnik, J.M.; Friedberg, J.W. A phase II trial to evaluate the efficacy of fostamatinib in patients with relapsed or refractory Diffuse Large B-Cell Lymphoma (DLBCL). Eur. J. Cancer, 2016, 54, 11-17.
[http://dx.doi.org/10.1016/j.ejca.2015.10.005] [PMID: 26707592]
[20]
Mandato, E.; Nunes, S.C.; Zaffino, F.; Casellato, A.; Macaccaro, P.; Tubi, L.Q.; Visentin, A.; Trentin, L.; Semenzato, G.; Piazza, F. CX-4945, a selective inhibitor of Casein Kinase 2, synergizes with B cell receptor signaling inhibitors in inducing diffuse large b cell lymphoma cell death. Curr. Cancer Drug Targets, 2018, 18(6), 608-616.
[http://dx.doi.org/10.2174/1568009617666170427110450] [PMID: 28460620]
[21]
Yang, Y.; Shaffer, A.L., III; Emre, N.C.; Ceribelli, M.; Zhang, M.; Wright, G.; Xiao, W.; Powell, J.; Platig, J.; Kohlhammer, H.; Young, R.M.; Zhao, H.; Yang, Y.; Xu, W.; Buggy, J.J.; Balasubramanian, S.; Mathews, L.A.; Shinn, P.; Guha, R.; Ferrer, M.; Thomas, C.; Waldmann, T.A.; Staudt, L.M. Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell, 2012, 21(6), 723-737.
[http://dx.doi.org/10.1016/j.ccr.2012.05.024] [PMID: 22698399]
[22]
Younes, A.; Thieblemont, C.; Morschhauser, F.; Flinn, I.; Friedberg, J.W.; Amorim, S.; Hivert, B.; Westin, J.; Vermeulen, J.; Bandyopadhyay, N.; de Vries, R.; Balasubramanian, S.; Hellemans, P.; Smit, J.W.; Fourneau, N.; Oki, Y. Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: A non-randomised, phase 1b study. Lancet Oncol., 2014, 15(9), 1019-1026.
[http://dx.doi.org/10.1016/S1470-2045(14)70311-0] [PMID: 25042202]
[23]
He, Y.; Li, J.; Ding, N.; Wang, X.; Deng, L.; Xie, Y.; Ying, Z.; Liu, W.; Ping, L.; Zhang, C.; Song, Y.; Zhu, J. Combination of Enzastaurin and Ibrutinib synergistically induces anti-tumor effects in diffuse large B cell lymphoma. J. Exp. Clin. Cancer Res., 2019, 38(1), 86.
[http://dx.doi.org/10.1186/s13046-019-1076-4] [PMID: 30777096]
[24]
Gaudio, E.; Tarantelli, C.; Kwee, I.; Barassi, C.; Bernasconi, E.; Rinaldi, A.; Ponzoni, M.; Cascione, L.; Targa, A.; Stathis, A.; Goodstal, S.; Zucca, E.; Bertoni, F. Combination of the MEK inhibitor pimasertib with BTK or PI3K-delta inhibitors is active in preclinical models of aggressive lymphomas. Ann. Oncol., 2016, 27(6), 1123-1128.
[http://dx.doi.org/10.1093/annonc/mdw131] [PMID: 26961147]
[25]
Mathews Griner, L.A.; Guha, R.; Shinn, P.; Young, R.M.; Keller, J.M.; Liu, D.; Goldlust, I.S.; Yasgar, A.; McKnight, C.; Boxer, M.B.; Duveau, D.Y.; Jiang, J.K.; Michael, S.; Mierzwa, T.; Huang, W.; Walsh, M.J.; Mott, B.T.; Patel, P.; Leister, W.; Maloney, D.J.; Leclair, C.A.; Rai, G.; Jadhav, A.; Peyser, B.D.; Austin, C.P.; Martin, S.E.; Simeonov, A.; Ferrer, M.; Staudt, L.M.; Thomas, C.J. High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cells. Proc. Natl. Acad. Sci. USA, 2014, 111(6), 2349-2354.
[http://dx.doi.org/10.1073/pnas.1311846111] [PMID: 24469833]
[26]
Ramachandiran, S.; Adon, A.; Guo, X.; Wang, Y.; Wang, H.; Chen, Z.; Kowalski, J.; Sunay, U.R.; Young, A.N.; Brown, T.; Mar, J.C.; Du, Y.; Fu, H.; Mann, K.P.; Natkunam, Y.; Boise, L.H.; Saavedra, H.I.; Lossos, I.S.; Bernal-Mizrachi, L. Chromosome instability in diffuse large B cell lymphomas is suppressed by activation of the noncanonical NF-κB pathway. Int. J. Cancer, 2015, 136(10), 2341-2351.
[http://dx.doi.org/10.1002/ijc.29301] [PMID: 25359525]
[27]
Wang, D.; Liu, P.; Zhang, Y.; Liu, H.Y.; Shen, D.; Che, Y.Q. Bone marrow molecular markers associated with relapsed/refractory activated B-cell-like diffuse large B-cell lymphoma. BioMed Res. Int., 2018, 20181042597.
[http://dx.doi.org/10.1155/2018/1042597]
[28]
Almaden, J.V.; Liu, Y.C.; Yang, E.; Otero, D.C.; Birnbaum, H.; Davis-Turak, J.; Asagiri, M.; David, M.; Goldrath, A.W.; Hoffmann, A. B-cell survival and development controlled by the coordination of NF-κB family members RelB and cRel. Blood, 2016, 127(10), 1276-1286.
[http://dx.doi.org/10.1182/blood-2014-10-606988] [PMID: 26773039]
[29]
Zhang, M.; Xu-Monette, Z.Y.; Li, L.; Manyam, G.C.; Visco, C.; Tzankov, A.; Wang, J.; Montes-Moreno, S.; Dybkaer, K.; Chiu, A.; Orazi, A.; Zu, Y.; Bhagat, G.; Richards, K.L.; Hsi, E.D.; Choi, W.W.; Han van Krieken, J.; Huh, J.; Ponzoni, M.; Ferreri, A.J.; Møller, M.B.; Parsons, B.M.; Winter, J.N.; Piris, M.A.; Medeiros, L.J.; Pham, L.V.; Young, K.H. RelA NF-κB subunit activation as a therapeutic target in diffuse large B-cell lymphoma. Aging (Albany NY), 2016, 8(12), 3321-3340.
[http://dx.doi.org/10.18632/aging.101121] [PMID: 27941215]
[30]
Hu, C.R.; Wang, J.H.; Wang, R.; Sun, Q.; Chen, L.B. Both FOXP1 and p65 expression are adverse risk factors in diffuse large B-cell lymphoma: A retrospective study in China. Acta Histochem., 2013, 115(2), 137-143.
[http://dx.doi.org/10.1016/j.acthis.2012.06.001] [PMID: 22809882]
[31]
Houldsworth, J.; Olshen, A.B.; Cattoretti, G.; Donnelly, G.B.; Teruya-Feldstein, J.; Qin, J.; Palanisamy, N.; Shen, Y.; Dyomina, K.; Petlakh, M.; Pan, Q.; Zelenetz, A.D.; Dalla-Favera, R.; Chaganti, R.S. Relationship between REL amplification, REL function, and clinical and biologic features in diffuse large B-cell lymphomas. Blood, 2004, 103(5), 1862-1868.
[http://dx.doi.org/10.1182/blood-2003-04-1359] [PMID: 14615382]
[32]
Li, L.; Xu-Monette, Z.Y.; Ok, C.Y.; Tzankov, A.; Manyam, G.C.; Sun, R.; Visco, C.; Zhang, M.; Montes-Moreno, S.; Dybkaer, K.; Chiu, A.; Orazi, A.; Zu, Y.; Bhagat, G.; Richards, K.L.; Hsi, E.D.; Choi, W.W.; van Krieken, J.H.; Huh, J.; Ponzoni, M.; Ferreri, A.J.; Møller, M.B.; Wang, J.; Parsons, B.M.; Winter, J.N.; Piris, M.A.; Pham, L.V.; Medeiros, L.J.; Young, K.H. Prognostic impact of c-Rel nuclear expression and REL amplification and crosstalk between c-Rel and the p53 pathway in diffuse large B-cell lymphoma. Oncotarget, 2015, 6(27), 23157-23180.
[http://dx.doi.org/10.18632/oncotarget.4319] [PMID: 26324762]
[33]
Niu, M.; Shen, Y.; Xu, X.; Yao, Y.; Fu, C.; Yan, Z.; Wu, Q.; Cao, J.; Sang, W.; Zeng, L.; Li, Z.; Liu, X.; Xu, K. Piperlongumine selectively suppresses ABC-DLBCL through inhibition of NF-κB p65 subunit nuclear import. Biochem. Biophys. Res. Commun., 2015, 462(4), 326-331.
[http://dx.doi.org/10.1016/j.bbrc.2015.04.136] [PMID: 25979358]
[34]
Zhang, M.; Xu-Monette, Z.Y.; Li, L.; Manyam, G.C.; Visco, C.; Tzankov, A.; Wang, J.; Montes-Moreno, S.; Dybkaer, K.; Chiu, A.; Orazi, A.; Zu, Y.; Bhagat, G.; Richards, K.L.; Hsi, E.D.; Choi, W.W.; Han van Krieken, J.; Huh, J.; Ponzoni, M.; Ferreri, A.J.; Møller, M.B.; Parsons, B.M.; Winter, J.N.; Piris, M.A.; Medeiros, L.J.; Pham, L.V.; Young, K.H. RelA NF-κB subunit activation as a therapeutic target in diffuse large B-cell lymphoma. Aging (Albany NY), 2016, 8(12), 3321-3340.
[http://dx.doi.org/10.18632/aging.101121]
[35]
Bose, P.; Batalo, M.S.; Holkova, B.; Grant, S. Bortezomib for the treatment of non-Hodgkin’s lymphoma. Expert Opin. Pharmacother., 2014, 15(16), 2443-2459.
[http://dx.doi.org/10.1517/14656566.2014.965142] [PMID: 25263936]
[36]
Ruan, J.; Martin, P.; Furman, R.R.; Lee, S.M.; Cheung, K.; Vose, J.M.; Lacasce, A.; Morrison, J.; Elstrom, R.; Ely, S.; Chadburn, A.; Cesarman, E.; Coleman, M.; Leonard, J.P. Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma. J. Clin. Oncol., 2011, 29(6), 690-697.
[http://dx.doi.org/10.1200/JCO.2010.31.1142] [PMID: 21189393]
[37]
Leonard, J.P.; Kolibaba, K.S.; Reeves, J.A.; Tulpule, A.; Flinn, I.W.; Kolevska, T.; Robles, R.; Flowers, C.R.; Collins, R.; DiBella, N.J.; Papish, S.W.; Venugopal, P.; Horodner, A.; Tabatabai, A.; Hajdenberg, J.; Park, J.; Neuwirth, R.; Mulligan, G.; Suryanarayan, K.; Esseltine, D.L.; de Vos, S. Randomized phase II study of R-CHOP with or without bortezomib in previously untreated patients with non-germinal center B-cell-like diffuse large B-cell lymphoma. J. Clin. Oncol., 2017, 35(31), 3538-3546.
[http://dx.doi.org/10.1200/JCO.2017.73.2784] [PMID: 28862883]
[38]
Davies, A.; Cummin, T.E.; Barrans, S.; Maishman, T.; Mamot, C.; Novak, U.; Caddy, J.; Stanton, L.; Kazmi-Stokes, S.; McMillan, A.; Fields, P.; Pocock, C.; Collins, G.P.; Stephens, R.; Cucco, F.; Clipson, A.; Sha, C.; Tooze, R.; Care, M.A.; Griffiths, G.; Du, M.Q.; Westhead, D.R.; Burton, C.; Johnson, P.W.M. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): An open-label, randomised, phase 3 trial. Lancet Oncol., 2019, 20(5), 649-662.
[http://dx.doi.org/10.1016/S1470-2045(18)30935-5] [PMID: 30948276]
[39]
Dasmahapatra, G.; Patel, H.; Dent, P.; Fisher, R.I.; Friedberg, J.; Grant, S. The Bruton tyrosine kinase (BTK) inhibitor PCI-32765 synergistically increases proteasome inhibitor activity in diffuse large-B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells sensitive or resistant to bortezomib [published correction appears in Br. J. Haematol., 2019, 184(5), 884-886].Br. J. Haematol., 2013,161 (1), 43-56.
[http://dx.doi.org/10.1111/bjh.12206]
[40]
Elstrom, R.L.; Andemariam, B.; Martin, P.; Ruan, J.; Shore, T.B.; Coleman, M.; Leonard, J.P.; Furman, R.R. Bortezomib in combination with rituximab, dexamethasone, ifosfamide, cisplatin and etoposide chemoimmunotherapy in patients with relapsed and primary refractory diffuse large B-cell lymphoma. Leuk. Lymphoma, 2012, 53(8), 1469-1473.
[http://dx.doi.org/10.3109/10428194.2012.656629] [PMID: 22263572]
[41]
Dasmahapatra, G.; Lembersky, D.; Kramer, L.; Fisher, R.I.; Friedberg, J.; Dent, P.; Grant, S. The pan-HDAC inhibitor vorinostat potentiates the activity of the proteasome inhibitor carfilzomib in human DLBCL cells in vitro and in vivo. Blood, 2010, 115(22), 4478-4487.
[http://dx.doi.org/10.1182/blood-2009-12-257261] [PMID: 20233973]
[42]
Dasmahapatra, G.; Patel, H.; Friedberg, J.; Quayle, S.N.; Jones, S.S.; Grant, S. In vitro and in vivo interactions between the HDAC6 inhibitor ricolinostat (ACY1215) and the irreversible proteasome inhibitor carfilzomib in non-Hodgkin lymphoma cells. Mol. Cancer Ther., 2014, 13(12), 2886-2897.
[http://dx.doi.org/10.1158/1535-7163.MCT-14-0220] [PMID: 25239935]
[43]
Dasmahapatra, G.; Lembersky, D.; Son, M.P.; Patel, H.; Peterson, D.; Attkisson, E.; Fisher, R.I.; Friedberg, J.W.; Dent, P.; Grant, S. Obatoclax interacts synergistically with the irreversible proteasome inhibitor carfilzomib in GC- and ABC-DLBCL cells in vitro and in vivo. Mol. Cancer Ther., 2012, 11(5), 1122-1132.
[http://dx.doi.org/10.1158/1535-7163.MCT-12-0021] [PMID: 22411899]
[44]
Gaurnier-Hausser, A.; Patel, R.; Baldwin, A.S.; May, M.J.; Mason, N.J. NEMO-binding domain peptide inhibits constitutive NF-κB activity and reduces tumor burden in a canine model of relapsed, refractory diffuse large B-cell lymphoma. Clin. Cancer Res., 2011, 17(14), 4661-4671.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-3310] [PMID: 21610150]
[45]
Habineza Ndikuyeze, G.; Gaurnier-Hausser, A.; Patel, R.; Baldwin, A.S.; May, M.J.; Flood, P.; Krick, E.; Propert, K.J.; Mason, N.J. A phase I clinical trial of systemically delivered NEMO binding domain peptide in dogs with spontaneous activated B-cell like diffuse large B-cell lymphoma. PLoS One, 2014, 9(5)e95404.
[http://dx.doi.org/10.1371/journal.pone.0095404] [PMID: 24798348]
[46]
Karmali, R.; Gordon, L.I. Molecular subtyping in diffuse Large B cell lymphoma: Closer to an approach of precision therapy. Curr. Treat. Options Oncol., 2017, 18(2), 11.
[http://dx.doi.org/10.1007/s11864-017-0449-1] [PMID: 28229364]
[47]
Jhanwar-Uniyal, M.; Wainwright, J.V.; Mohan, A.L.; Tobias, M.E.; Murali, R.; Gandhi, C.D.; Schmidt, M.H. Diverse signaling mechanisms of mTOR complexes: mTORC1 and mTORC2 in forming a formidable relationship. Adv. Biol. Regul., 2019, 72, 51-62.
[http://dx.doi.org/10.1016/j.jbior.2019.03.003] [PMID: 31010692]
[48]
Mazan-Mamczarz, K.; Peroutka, R.J.; Steinhardt, J.J.; Gidoni, M.; Zhang, Y.; Lehrmann, E.; Landon, A.L.; Dai, B.; Houng, S.; Muniandy, P.A.; Efroni, S.; Becker, K.G.; Gartenhaus, R.B. Distinct inhibitory effects on mTOR signaling by ethanol and INK128 in diffuse large B-cell lymphoma. Cell Commun. Signal., 2015, 13, 15.
[http://dx.doi.org/10.1186/s12964-015-0091-0] [PMID: 25849580]
[49]
Zang, C.; Eucker, J.; Liu, H.; Müller, A.; Possinger, K.; Scholz, C.W. Concurrent inhibition of PI3-kinase and mTOR induces cell death in diffuse large B cell lymphomas, a mechanism involving down regulation of Mcl-1. Cancer Lett., 2013, 339(2), 288-297.
[http://dx.doi.org/10.1016/j.canlet.2012.11.013] [PMID: 23200668]
[50]
Paul, J.; Soujon, M.; Wengner, A.M.; Zitzmann-Kolbe, S.; Sturz, A.; Haike, K.; Keng Magdalene, K.H.; Tan, S.H.; Lange, M.; Tan, S.Y.; Mumberg, D.; Lim, S.T.; Ziegelbauer, K.; Liu, N. Simultaneous inhibition of PI3Kδ and PI3Kα induces ABC-DLBCL regression by blocking BCR-dependent and independent activation of NF-KB and AKT. Cancer Cell, 2017, 31(1), 64-78.
[http://dx.doi.org/10.1016/j.ccell.2016.12.003] [PMID: 28073005]
[51]
Mao, Y.; Xu, L.; Wang, J.; Zhang, L.; Hou, N.; Xu, J.; Wang, L.; Yang, S.; Chen, Y.; Xiong, L.; Zhu, J.; Fan, W.; Xu, J. ROR1 associates unfavorable prognosis and promotes lymphoma growth in DLBCL by affecting PI3K/Akt/mTOR signaling pathway. Biofactors, 2019, 45(3), 416-426.
[http://dx.doi.org/10.1002/biof.1498] [PMID: 30801854]
[52]
Xu, Z.Z.; Xia, Z.G.; Wang, A.H.; Wang, W.F.; Liu, Z.Y.; Chen, L.Y.; Li, J.M. Activation of the PI3K/AKT/mTOR pathway in diffuse large B cell lymphoma: Clinical significance and inhibitory effect of rituximab. Ann. Hematol., 2013, 92(10), 1351-1358.
[http://dx.doi.org/10.1007/s00277-013-1770-9] [PMID: 23636313]
[53]
Ma, Y.; Zhang, P.; Gao, Y.; Fan, H.; Zhang, M.; Wu, J. Evaluation of AKT phosphorylation and PTEN loss and their correlation with the resistance of rituximab in DLBCL. Int. J. Clin. Exp. Pathol., 2015, 8(11), 14875-14884.
[PMID: 26823817]
[54]
Hong, J.Y.; Hong, M.E.; Choi, M.K.; Kim, Y.S.; Chang, W.; Maeng, C.H.; Park, S.; Lee, S.J.; Do, I.G.; Jo, J.S.; Jung, S.H.; Kim, S.J.; Ko, Y.H.; Kim, W.S. The impact of activated p-AKT expression on clinical outcomes in diffuse large B-cell lymphoma: A clinicopathological study of 262 cases. Ann. Oncol., 2014, 25(1), 182-188.
[http://dx.doi.org/10.1093/annonc/mdt530] [PMID: 24356628]
[55]
Hasselblom, S.; Hansson, U.; Olsson, M.; Torén, L.; Bergström, A.; Nilsson-Ehle, H.; Andersson, P.O. High immunohistochemical expression of p-AKT predicts inferior survival in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Br. J. Haematol., 2010, 149(4), 560-568.
[http://dx.doi.org/10.1111/j.1365-2141.2010.08123.x] [PMID: 20201946]
[56]
Petrich, A.M.; Leshchenko, V.; Kuo, P.Y.; Xia, B.; Thirukonda, V.K.; Ulahannan, N.; Gordon, S.; Fazzari, M.J.; Ye, B.H.; Sparano, J.A.; Parekh, S. Akt Inhibitors MK-2206 and Nelfinavir overcome mTOR inhibitor resistance in DLBCL. Clin. Cancer Res., 2012, 18(9), 2534-2544.
[http://dx.doi.org/10.1158/1078-0432]
[57]
Zang, C.; Eucker, J.; Liu, H.; Coordes, A.; Lenarz, M.; Possinger, K.; Scholz, C.W. Inhibition of pan-class I phosphatidyl-inositol-3-kinase by NVP-BKM120 effectively blocks proliferation and induces cell death in diffuse large B-cell lymphoma. Leuk. Lymphoma, 2014, 55(2), 425-434.
[http://dx.doi.org/10.3109/10428194.2013.806800] [PMID: 23721513]
[58]
Rodon, J.; Braña, I.; Siu, L.L.; De Jonge, M.J.; Homji, N.; Mills, D.; Di Tomaso, E.; Sarr, C.; Trandafir, L.; Massacesi, C.; Eskens, F.; Bendell, J.C. Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. Invest. New Drugs, 2014, 32(4), 670-681.
[http://dx.doi.org/10.1007/s10637-014-0082-9] [PMID: 24652201]
[59]
Younes, A.; Salles, G.; Martinelli, G.; Bociek, R.G.; Barrigon, D.C.; Barca, E.G.; Turgut, M.; Gerecitano, J.; Kong, O.; Pisal, C.B.; Tavorath, R.; Kim, W.S. Pan-phosphatidylinositol 3-kinase inhibition with buparlisib in patients with relapsed or refractory non-Hodgkin lymphoma. Haematologica, 2017, 102(12), 2104-2112.
[http://dx.doi.org/10.3324/haematol.2017.169656] [PMID: 28971900]
[60]
Paul, J.; Soujon, M.; Wengner, A.M.; Zitzmann-Kolbe, S.; Sturz, A.; Haike, K.; Keng Magdalene, K.H.; Tan, S.H.; Lange, M.; Tan, S.Y.; Mumberg, D.; Lim, S.T.; Ziegelbauer, K.; Liu, N. Simultaneous inhibition of PI3Kδ and PI3Kα induces ABC-DLBCL regression by blocking BCR-dependent and -independent activation of NF-κB and AKT. Cancer Cell, 2017, 31(1), 64-78.
[http://dx.doi.org/10.1016/j.ccell.2016.12.003] [PMID: 28073005]
[61]
Patnaik, A.; Appleman, L.J.; Tolcher, A.W.; Papadopoulos, K.P.; Beeram, M.; Rasco, D.W.; Weiss, G.J.; Sachdev, J.C.; Chadha, M.; Fulk, M.; Ejadi, S.; Mountz, J.M.; Lotze, M.T.; Toledo, F.G.; Chu, E.; Jeffers, M.; Peña, C.; Xia, C.; Reif, S.; Genvresse, I.; Ramanathan, R.K. First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin’s lymphomas. Ann. Oncol., 2016, 27(10), 1928-1940.
[http://dx.doi.org/10.1093/annonc/mdw282] [PMID: 27672108]
[62]
Johnston, P.B.; LaPlant, B.; McPhail, E.; Habermann, T.M.; Inwards, D.J.; Micallef, I.N.; Colgan, J.P.; Nowakowski, G.S.; Ansell, S.M.; Witzig, T.E. Everolimus combined with R-CHOP-21 for new, untreated, diffuse large B-cell lymphoma (NCCTG 1085 [Alliance]): Safety and efficacy results of a phase 1 and feasibility trial. Lancet Haematol., 2016, 3(7), e309-e316.
[http://dx.doi.org/10.1016/S2352-3026(16)30040-0] [PMID: 27374464]
[63]
Barnes, J.A.; Jacobsen, E.; Feng, Y.; Freedman, A.; Hochberg, E.P.; LaCasce, A.S.; Armand, P.; Joyce, R.; Sohani, A.R.; Rodig, S.J.; Neuberg, D.; Fisher, D.C.; Abramson, J.S. Everolimus in combination with rituximab induces complete responses in heavily pretreated diffuse large B-cell lymphoma. Haematologica, 2013, 98(4), 615-619.
[http://dx.doi.org/10.3324/haematol.2012.075184] [PMID: 23144193]
[64]
Witzig, T.E.; Tobinai, K.; Rigacci, L.; Ikeda, T.; Vanazzi, A.; Hino, M.; Shi, Y.; Mayer, J.; Costa, L.J.; Bermudez Silva, C.D.; Zhu, J.; Belada, D.; Bouabdallah, K.; Kattan, J.G.; Kuruvilla, J.; Kim, W.S.; Larouche, J.F.; Ogura, M.; Ozcan, M.; Fayad, L.; Wu, C.; Fan, J.; Louveau, A.L.; Voi, M.; Cavalli, F. Adjuvant everolimus in high-risk diffuse large B-cell lymphoma: Final results from the PILLAR-2 randomized phase III trial. Ann. Oncol., 2018, 29(3), 707-714.
[http://dx.doi.org/10.1093/annonc/mdx764] [PMID: 29253068]
[65]
Fenske, T.S.; Shah, N.M.; Kim, K.M.; Saha, S.; Zhang, C.; Baim, A.E.; Farnen, J.P.; Onitilo, A.A.; Blank, J.H.; Ahuja, H.; Wassenaar, T.; Qamar, R.; Mansky, P.; Traynor, A.M.; Mattison, R.J.; Kahl, B.S. A phase 2 study of weekly temsirolimus and bortezomib for relapsed or refractory B-cell non-Hodgkin lymphoma: A Wisconsin Oncology Network study. Cancer, 2015, 121(19), 3465-3471.
[http://dx.doi.org/10.1002/cncr.29502] [PMID: 26079295]
[66]
Gupta, M.; Ansell, S.M.; Novak, A.J.; Kumar, S.; Kaufmann, S.H.; Witzig, T.E. Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2. Blood, 2009, 114(14), 2926-2935.
[http://dx.doi.org/10.1182/blood-2009-05-220889] [PMID: 19641186]
[67]
Mortensen, D.S.; Fultz, K.E.; Xu, S.; Xu, W.; Packard, G.; Khambatta, G.; Gamez, J.C.; Leisten, J.; Zhao, J.; Apuy, J.; Ghoreishi, K.; Hickman, M.; Narla, R.K.; Bissonette, R.; Richardson, S.; Peng, S.X.; Perrin-Ninkovic, S.; Tran, T.; Shi, T.; Yang, W.Q.; Tong, Z.; Cathers, B.E.; Moghaddam, M.F.; Canan, S.S.; Worland, P.; Sankar, S.; Raymon, H.K. CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and in vivo characterization. Mol. Cancer Ther., 2015, 14(6), 1295-1305.
[http://dx.doi.org/10.1158/1535-7163.MCT-14-1052] [PMID: 25855786]
[68]
Jin, Z.; Qing, K.; Ouyang, Y.; Liu, Z.; Wang, W.; Li, X.; Xu, Z.; Li, J. Low dose of lenalidmide and PI3K/mTOR inhibitor trigger synergistic cytoxicity in activated B cell-like subtype of diffuse large B cell lymphoma. J. Exp. Clin. Cancer Res., 2016, 35, 52.
[http://dx.doi.org/10.1186/s13046-016-0327-x] [PMID: 27009084]
[69]
Qing, K.; Jin, Z.; Fu, W.; Wang, W.; Liu, Z.; Li, X.; Xu, Z.; Li, J. Synergistic effect of oridonin and a PI3K/mTOR inhibitor on the non-germinal center B cell-like subtype of diffuse large B cell lymphoma. J. Hematol. Oncol., 2016, 9(1), 72.
[http://dx.doi.org/10.1186/s13045-016-0303-0] [PMID: 27554093]
[70]
Cornez, I.; Yajnanarayana, S.P.; Wolf, A.M.; Wolf, D. JAK/STAT disruption induces immune-deficiency: Rationale for the development of JAK inhibitors as immunosuppressive drugs. Mol. Cell Endocrinol, 2017, S0303-7207(7), 30048-30045.
[71]
Ok, C.Y.; Chen, J.; Xu-Monette, Z.Y.; Tzankov, A.; Manyam, G.C.; Li, L.; Visco, C.; Montes-Moreno, S.; Dybkaer, K.; Chiu, A.; Orazi, A.; Zu, Y.; Bhagat, G.; Richards, K.L.; Hsi, E.D.; Choi, W.W.; van Krieken, J.H.; Huh, J.; Zhao, X.; Ponzoni, M.; Ferreri, A.J.; Bertoni, F.; Farnen, J.P.; Møller, M.B.; Piris, M.A.; Winter, J.N.; Medeiros, L.J.; Young, K.H. Clinical implications of phosphorylated STAT3 expression in de novo diffuse large B-cell lymphoma. Clin. Cancer Res., 2014, 20(19), 5113-5123.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-0683] [PMID: 25124685]
[72]
Rui, L.; Drennan, A.C.; Ceribelli, M.; Zhu, F.; Wright, G.W.; Huang, D.W.; Xiao, W.; Li, Y.; Grindle, K.M.; Lu, L.; Hodson, D.J.; Shaffer, A.L.; Zhao, H.; Xu, W.; Yang, Y.; Staudt, L.M. Epigenetic gene regulation by Janus kinase 1 in diffuse large B-cell lymphoma. Proc. Natl. Acad. Sci. USA, 2016, 113(46), E7260-E7267.
[http://dx.doi.org/10.1073/pnas.1610970113] [PMID: 27799566]
[73]
Lin, S. YuJun, L.; XiaoMing, X.; WenWen, R. Expression and significance of leptin receptor, p-STAT3 and p-AKT in diffuse large B-cell lymphoma. Acta Histochem., 2014, 116(1), 126-130.
[http://dx.doi.org/10.1016/j.acthis.2013.06.003] [PMID: 24054064]
[74]
Ding, B.B.; Yu, J.J.; Yu, R.Y.; Mendez, L.M.; Shaknovich, R.; Zhang, Y.; Cattoretti, G.; Ye, B.H. Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas. Blood, 2008, 111(3), 1515-1523.
[http://dx.doi.org/10.1182/blood-2007-04-087734] [PMID: 17951530]
[75]
Gupta, M.; Han, J.J.; Stenson, M.; Maurer, M.; Wellik, L.; Hu, G.; Ziesmer, S.; Dogan, A.; Witzig, T.E. Elevated serum IL-10 levels in diffuse large B-cell lymphoma: A mechanism of aberrant JAK2 activation. Blood, 2012, 119(12), 2844-2853.
[http://dx.doi.org/10.1182/blood-2011-10-388538] [PMID: 22323454]
[76]
Wu, Z.L.; Song, Y.Q.; Shi, Y.F.; Zhu, J. High nuclear expression of STAT3 is associated with unfavorable prognosis in diffuse large B-cell lymphoma. J. Hematol. Oncol., 2011, 4(1), 31.
[http://dx.doi.org/10.1186/1756-8722-4-31] [PMID: 21806788]
[77]
Huang, X.; Meng, B.; Iqbal, J.; Ding, B.B.; Perry, A.M.; Cao, W.; Smith, L.M.; Bi, C.; Jiang, C.; Greiner, T.C.; Weisenburger, D.D.; Rimsza, L.; Rosenwald, A.; Ott, G.; Delabie, J.; Campo, E.; Braziel, R.M.; Gascoyne, R.D.; Cook, J.R.; Tubbs, R.R.; Jaffe, E.S.; Armitage, J.O.; Vose, J.M.; Staudt, L.M.; McKeithan, T.W.; Chan, W.C.; Ye, B.H.; Fu, K. Activation of the STAT3 signaling pathway is associated with poor survival in diffuse large B-cell lymphoma treated with R-CHOP. J. Clin. Oncol., 2013, 31(36), 4520-4528.
[http://dx.doi.org/10.1200/JCO.2012.45.6004] [PMID: 24220563]
[78]
Scuto, A.; Kujawski, M.; Kowolik, C.; Krymskaya, L.; Wang, L.; Weiss, L.M.; Digiusto, D.; Yu, H.; Forman, S.; Jove, R. STAT3 inhibition is a therapeutic strategy for ABC-like diffuse large B-cell lymphoma. Cancer Res., 2011, 71(9), 3182-3188.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-2380] [PMID: 21521803]
[79]
Hart, S.; Goh, K.C.; Novotny-Diermayr, V.; Hu, C.Y.; Hentze, H.; Tan, Y.C.; Madan, B.; Amalini, C.; Loh, Y.K.; Ong, L.C.; William, A.D.; Lee, A.; Poulsen, A.; Jayaraman, R.; Ong, K.H.; Ethirajulu, K.; Dymock, B.W.; Wood, J.W. SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies. Leukemia, 2011, 25(11), 1751-1759.
[http://dx.doi.org/10.1038/leu.2011.148] [PMID: 21691275]
[80]
Younes, A.; Romaguera, J.; Fanale, M.; McLaughlin, P.; Hagemeister, F.; Copeland, A.; Neelapu, S.; Kwak, L.; Shah, J.; de Castro Faria, S.; Hart, S.; Wood, J.; Jayaraman, R.; Ethirajulu, K.; Zhu, J. Phase I study of a novel oral Janus kinase 2 inhibitor, SB1518, in patients with relapsed lymphoma: Evidence of clinical and biologic activity in multiple lymphoma subtypes. J. Clin. Oncol., 2012, 30(33), 4161-4167.
[http://dx.doi.org/10.1200/JCO.2012.42.5223] [PMID: 22965964]
[81]
Beck, D.; Zobel, J.; Barber, R.; Evans, S.; Lezina, L.; Allchin, R.L.; Blades, M.; Elliott, R.; Lord, C.J.; Ashworth, A.; Porter, A.C.; Wagner, S.D. Synthetic lethal screen demonstrates that a JAK2 Inhibitor Suppresses a BCL6-dependent IL10RA/JAK2/STAT3 pathway in high grade B-cell Lymphoma. J. Biol. Chem., 2016, 291(32), 16686-16698.
[http://dx.doi.org/10.1074/jbc.M116.736868] [PMID: 27268052]
[82]
Lu, Z.; Hong, C.C.; Jark, P.C.; Assumpção, A.L.F.V.; Bollig, N.; Kong, G.; Pan, X. JAK1/2 inhibitors AZD1480 and CYT387 inhibit canine B-cell lymphoma growth by increasing apoptosis and disrupting cell proliferation. J. Vet. Intern. Med., 2017, 31(6), 1804-1815.
[http://dx.doi.org/10.1111/jvim.14837] [PMID: 28960447]
[83]
Ma, J.; Xing, W.; Coffey, G.; Dresser, K.; Lu, K.; Guo, A.; Raca, G.; Pandey, A.; Conley, P.; Yu, H.; Wang, Y.L. Cerdulatinib, a novel dual SYK/JAK kinase inhibitor, has broad anti-tumor activity in both ABC and GCB types of diffuse large B cell lymphoma. Oncotarget, 2015, 6(41), 43881-43896.
[http://dx.doi.org/10.18632/oncotarget.6316] [PMID: 26575169]
[84]
Coffey, G.P.; Feng, J.; Betz, A.; Pandey, A.; Birrell, M.; Leeds, J.M.; Der, K.; Kadri, S.; Lu, P.; Segal, J.; Wang, Y.L.; Michelson, G.; Curnutte, J.T.; Conley, P.B. Cerdulatinib pharmacodynamics and relationships to tumor response following oral dosing in patients with relapsed/refractory B-cell malignancies. Clin. Cancer Res., 2019, 25(4), 1174-1184.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-1047] [PMID: 30333224]
[85]
Reilley, M.J.; McCoon, P.; Cook, C.; Lyne, P.; Kurzrock, R.; Kim, Y.; Woessner, R.; Younes, A.; Nemunaitis, J.; Fowler, N.; Curran, M.; Liu, Q.; Zhou, T.; Schmidt, J.; Jo, M.; Lee, S.J.; Yamashita, M.; Hughes, S.G.; Fayad, L.; Piha-Paul, S.; Nadella, M.V.P.; Xiao, X.; Hsu, J.; Revenko, A.; Monia, B.P.; MacLeod, A.R.; Hong, D.S. STAT3 antisense oligonucleotide AZD9150 in a subset of patients with heavily pretreated lymphoma: Results of a phase 1b trial. J. Immunother. Cancer, 2018, 6(1), 119.
[http://dx.doi.org/10.1186/s40425-018-0436-5] [PMID: 30446007]
[86]
Ge, X.; Sui, X.; Fang, X.; Jiang, Y.; Ding, M.; Liu, X.; Wang, X. A preliminary study on metadherin as a potential marker for progression of diffuse large B cell lymphoma. Genet. Test. Mol. Biomarkers, 2018, 22(8), 481-486.
[http://dx.doi.org/10.1089/gtmb.2018.0071] [PMID: 30117777]
[87]
Liu, X.; Huang, Y.; Zhang, Y.; Li, X.; Liu, C.; Huang, S.; Xu, D.; Wu, Y.; Liu, X. T-cell factor (TCF/LEF1) binding elements (TBEs) of FasL (Fas ligand or CD95 ligand) bind and cluster Fas (CD95) and form complexes with the TCF-4 and b-catenin transcription factors in vitro and in vivo which result in triggering cell death and/or cell activation. Cell. Mol. Neurobiol., 2016, 36(6), 1001-1013.
[http://dx.doi.org/10.1007/s10571-015-0290-7] [PMID: 27090258]
[88]
Bognar, M.K.; Vincendeau, M.; Erdmann, T.; Seeholzer, T.; Grau, M.; Linnemann, J.R.; Ruland, J.; Scheel, C.H.; Lenz, P.; Ott, G.; Lenz, G.; Hauck, S.M.; Krappmann, D. Oncogenic CARMA1 couples NF-κB and β-catenin signaling in diffuse large B-cell lymphomas. Oncogene, 2016, 35(32), 4269-4281.
[http://dx.doi.org/10.1038/onc.2015.493] [PMID: 26776161]
[89]
Ge, X.; Lv, X.; Feng, L.; Liu, X.; Wang, X. High expression and nuclear localization of β-catenin in diffuse large B-cell lymphoma. Mol. Med. Rep., 2012, 5(6), 1433-1437.
[http://dx.doi.org/10.3892/mmr.2012.835] [PMID: 22427053]
[90]
Karmali, R.; Chukkapalli, V.; Gordon, L.I.; Borgia, J.A.; Ugolkov, A.; Mazar, A.P.; Giles, F.J. GSK-3β inhibitor, 9-ING-41, reduces cell viability and halts proliferation of B-cell lymphoma cell lines as a single agent and in combination with novel agents. Oncotarget, 2017, 8(70), 114924-114934.
[http://dx.doi.org/10.18632/oncotarget.22414] [PMID: 29383130]
[91]
Robertson, M.J.; Kahl, B.S.; Vose, J.M.; de Vos, S.; Laughlin, M.; Flynn, P.J.; Rowland, K.; Cruz, J.C.; Goldberg, S.L.; Musib, L.; Darstein, C.; Enas, N.; Kutok, J.L.; Aster, J.C.; Neuberg, D.; Savage, K.J.; LaCasce, A.; Thornton, D.; Slapak, C.A.; Shipp, M.A. Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma. J. Clin. Oncol., 2007, 25(13), 1741-1746.
[http://dx.doi.org/10.1200/JCO.2006.09.3146] [PMID: 17389337]
[92]
Hainsworth, J.D.; Arrowsmith, E.R.; McCleod, M.; Hsi, E.D.; Hamid, O.; Shi, P.; Lin, B.K.; Fayad, L.E. A randomized, phase 2 study of R-CHOP plus enzastaurin vs R-CHOP in patients with intermediate- or high-risk diffuse large B-cell lymphoma. Leuk. Lymphoma, 2016, 57(1), 216-218.
[http://dx.doi.org/10.3109/10428194.2015.1045898] [PMID: 25956042]
[93]
Crump, M.; Leppä, S.; Fayad, L.; Lee, J.J.; Di Rocco, A.; Ogura, M.; Hagberg, H.; Schnell, F.; Rifkin, R.; Mackensen, A.; Offner, F.; Pinter-Brown, L.; Smith, S.; Tobinai, K.; Yeh, S.P.; Hsi, E.D.; Nguyen, T.; Shi, P.; Hahka-Kemppinen, M.; Thornton, D.; Lin, B.; Kahl, B.; Schmitz, N.; Savage, K.J.; Habermann, T. Randomized, Double-blind, phase III trial of enzastaurin versus placebo in patients achieving remission after first-line therapy for high-risk diffuse large B-cell lymphoma. J. Clin. Oncol., 2016, 34(21), 2484-2492.
[http://dx.doi.org/10.1200/JCO.2015.65.7171] [PMID: 27217449]
[94]
Larriba, M.J.; González-Sancho, J.M.; Barbáchano, A.; Niell, N.; Ferrer-Mayorga, G.; Muñoz, A.; Vitamin, D. Is a multilevel repressor of Wnt/b-catenin signaling in cancer cells. Cancers (Basel), 2013, 5(4), 1242-1260.
[http://dx.doi.org/10.3390/cancers5041242] [PMID: 24202444]
[95]
Kozielewicz, P.; Grafton, G.; Kutner, A.; Curnow, S.J.; Gordon, J.; Barnes, N.M. Novel vitamin D analogues; cytotoxic and anti-proliferative activity against a diffuse large B-cell lymphoma cell line and B-cells from healthy donors. J. Steroid Biochem. Mol. Biol., 2016, 164, 98-105.
[http://dx.doi.org/10.1016/j.jsbmb.2015.10.015] [PMID: 26485664]
[96]
Hohaus, S.; Tisi, M.C.; Bellesi, S.; Maiolo, E.; Alma, E.; Tartaglia, G.; Corrente, F.; Cuccaro, A.; D’Alo’, F.; Basile, U.; Larocca, L.M.; De Stefano, V. Vitamin D deficiency and supplementation in patients with aggressive B-cell lymphomas treated with immunochemotherapy. Cancer Med., 2018, 7(1), 270-281.
[http://dx.doi.org/10.1002/cam4.1166] [PMID: 29271084]
[97]
Zhang, Y.; Wang, C.P.; Ding, X.X.; Wang, N.; Ma, F.; Jiang, J.H.; Wang, Q.D.; Chang, J.B. FNC, a novel nucleoside analogue, blocks invasion of aggressive non-Hodgkin lymphoma cell lines via inhibition of the Wnt/β-catenin signaling pathway. Asian Pac. J. Cancer Prev., 2014, 15(16), 6829-6835.
[http://dx.doi.org/10.7314/APJCP.2014.15.16.6829] [PMID: 25169533]
[98]
Xie, Y.; Bulbul, M.A.; Ji, L.; Inouye, C.M.; Groshen, S.G.; Tulpule, A.; O’Malley, D.P.; Wang, E.; Siddiqi, I.N. p53 expression is a strong marker of inferior survival in de novo diffuse large B-cell lymphoma and may have enhanced negative effect with MYC coexpression: A single institutional clinicopathologic study. Am. J. Clin. Pathol., 2014, 141(4), 593-604.
[http://dx.doi.org/10.1309/AJCPPHMZ6VHF0WQV] [PMID: 24619762]
[99]
Sun, B.; Ross, S.M.; Rowley, S.; Adeleye, Y.; Clewell, R.A. Contribution of ATM and ATR kinase pathways to p53-mediated response in etoposide and methyl methanesulfonate induced DNA damage. Environ. Mol. Mutagen., 2017, 58(2), 72-83.
[http://dx.doi.org/10.1002/em.22070] [PMID: 28195382]
[100]
Wang, X.J.; Bueso-Ramos, C.E.; Tang, G.; Wang, S.; Oki, Y.; Desai, P.; Khoury, J.D.; Miranda, R.N.; Tang, Z.; Reddy, N.; Li, S.; Li, S.; Jeffrey Medeiros, L. P53 expression correlates with poorer survival and augments the negative prognostic effect of MYC rearrangement, expression or concurrent MYC/BCL2 expression in diffuse large B-cell lymphoma. Mod. Pathol., 2017, 30(2), 194-203.
[http://dx.doi.org/10.1038/modpathol.2016.178] [PMID: 27739436]
[101]
Xu-Monette, Z.Y.; Wu, L.; Visco, C.; Tai, Y.C.; Tzankov, A.; Liu, W.M.; Montes-Moreno, S.; Dybkaer, K.; Chiu, A.; Orazi, A.; Zu, Y.; Bhagat, G.; Richards, K.L.; Hsi, E.D.; Zhao, X.F.; Choi, W.W.; Zhao, X.; van Krieken, J.H.; Huang, Q.; Huh, J.; Ai, W.; Ponzoni, M.; Ferreri, A.J.; Zhou, F.; Kahl, B.S.; Winter, J.N.; Xu, W.; Li, J.; Go, R.S.; Li, Y.; Piris, M.A.; Møller, M.B.; Miranda, R.N.; Abruzzo, L.V.; Medeiros, L.J.; Young, K.H. Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: Report from an international DLBCL Rituximab-CHOP consortium program study. Blood, 2012, 120(19), 3986-3996.
[http://dx.doi.org/10.1182/blood-2012-05-433334] [PMID: 22955915]
[102]
Vassilev, L.T.; Vu, B.T.; Graves, B.; Carvajal, D.; Podlaski, F.; Filipovic, Z.; Kong, N.; Kammlott, U.; Lukacs, C.; Klein, C.; Fotouhi, N.; Liu, E.A. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science, 2004, 303(5659), 844-848.
[http://dx.doi.org/10.1126/science.1092472] [PMID: 14704432]
[103]
Drakos, E.; Singh, R.R.; Rassidakis, G.Z.; Schlette, E.; Li, J.; Claret, F.X.; Ford, R.J., Jr; Vega, F.; Medeiros, L.J. Activation of the p53 pathway by the MDM2 inhibitor nutlin-3a overcomes BCL2 overexpression in a preclinical model of diffuse large B-cell lymphoma associated with t(14;18)(q32;q21). Leukemia, 2011, 25(5), 856-867.
[http://dx.doi.org/10.1038/leu.2011.28] [PMID: 21394100]
[104]
Sosin, A.M.; Burger, A.M.; Siddiqi, A.; Abrams, J.; Mohammad, R.M.; Al-Katib, A.M. HDM2 antagonist MI-219 (spiro-oxindole), but not Nutlin-3 (cis-imidazoline), regulates p53 through enhanced HDM2 autoubiquitination and degradation in human malignant B-cell lymphomas. J. Hematol. Oncol., 2012, 5, 57.
[http://dx.doi.org/10.1186/1756-8722-5-57] [PMID: 22989009]
[105]
Vu, B.; Wovkulich, P.; Pizzolato, G.; Lovey, A.; Ding, Q.; Jiang, N.; Liu, J.J.; Zhao, C.; Glenn, K.; Wen, Y.; Tovar, C.; Packman, K.; Vassilev, L.; Graves, B. Discovery of RG7112: A small-molecule MDM2 inhibitor in clinical development. ACS Med. Chem. Lett., 2013, 4(5), 466-469.
[http://dx.doi.org/10.1021/ml4000657] [PMID: 24900694]
[106]
Ray-Coquard, I.; Blay, J-Y.; Italiano, A.; Le Cesne, A.; Penel, N.; Zhi, J.; Heil, F.; Rueger, R.; Graves, B.; Ding, M.; Geho, D.; Middleton, S.A.; Vassilev, L.T.; Nichols, G.L.; Bui, B.N. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol., 2012, 13(11), 1133-1140.
[http://dx.doi.org/10.1016/S1470-2045(12)70474-6] [PMID: 23084521]
[107]
Andreeff, M.; Kelly, K.R.; Yee, K.; Assouline, S.; Strair, R.; Popplewell, L.; Bowen, D.; Martinelli, G.; Drummond, M.W.; Vyas, P.; Kirschbaum, M.; Iyer, S.P.; Kojima, K.; Geho, D.; Blotner, S.; Cheng, S.; Vassilev, L.; Ding, M.; Zhi, J.; Middleton, S.; Nichols, G. Results of the phase 1 Trial of RG7112, a small-molecule MDM2 antagonist, in acute leukemia. 54th Annual Meeting of the American Society of Hematology, Georgia, Atlanta December 8-112012.
[108]
Richmond, J.; Carol, H.; Evans, K.; High, L.; Mendomo, A.; Robbins, A.; Meyer, C.; Venn, N.C.; Marschalek, R.; Henderson, M.; Sutton, R.; Kurmasheva, R.T.; Kees, U.R.; Houghton, P.J.; Smith, M.A.; Lock, R.B. effective targeting of the P53/MDM2 axis in preclinical models of infant MLL-rearranged acute lymphoblastic leukemia. Clin. Cancer Res., 2015, 21(6), 1395-1405.
[http://dx.doi.org/10.1158/1078-0432]
[109]
Herting, F.; Herter, S.; Friess, T.; Muth, G.; Bacac, M.; Sulcova, J.; Umana, P.; Dangl, M.; Klein, C. Antitumour activity of the glycoengineered type II anti-CD20 antibody obinutuzumab (GA101) in combination with the MDM2-selective antagonist idasanutlin (RG7388). Eur. J. Haematol., 2016, 97(5), 461-470.
[http://dx.doi.org/10.1111/ejh.12756] [PMID: 26993060]
[110]
Wang, Y.; Li, Y.J.; Jiang, W.Q.; Rao, H.L.; Huang, J.J.; Xia, Y.; Bi, X.; Sun, P.; Huang, H.Q.; Lin, T.Y.; Guan, Z.Z.; Li, Z.M. Expression of BAFF-R, but not BAFF, is an independent prognostic factor in diffuse large B-cell lymphoma patients treated with R-CHOP. Ann. Hematol., 2015, 94(11), 1865-1873.
[http://dx.doi.org/10.1007/s00277-015-2490-0] [PMID: 26327569]
[111]
Huang, Y.; Zou, Y.; Lin, L.; Ma, X.; Zheng, R. miR101 regulates the cell proliferation and apoptosis in diffuse large Bcell lymphoma by targeting MEK1 via regulation of the ERK/MAPK signaling pathway. Oncol. Rep., 2019, 41(1), 377-386.
[http://dx.doi.org/10.3892/or.2018.6821] [PMID: 30365139]
[112]
Brown, P.J.; Wong, K.K.; Felce, S.L. FOXP1 suppresses immune response signatures and MHC class II expression in activated B-cell-like diffuse large B-cell lymphomas. Leukemia, 2016, 30(3), 605-616.
[http://dx.doi.org/10.1038/leu.2015.299]

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