The mTORC1 inhibitor everolimus has antitumor activity in vitro and produces tumor responses in patients with relapsed T-cell lymphoma by Thomas E. Witzig,

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The mTORC1 inhibitor everolimus has antitumor activity in vitro and produces tumor responses in patients with relapsed T-cell lymphoma by Thomas E. Witzig, Craig Reeder, Jing Jing Han, Betsy LaPlant, Mary Stenson, Han W. Tun, William Macon, Stephen M. Ansell, Thomas M. Habermann, David J. Inwards, Ivana N. Micallef, Patrick B. Johnston, Luis F. Porrata, Joseph P. Colgan, Svetomir Markovic, Grzegorz S. Nowakowski, and Mamta Gupta Blood Volume 126(3):328-335 July 16, 2015 ©2015 by American Society of Hematology

Activation of mTOR signaling in TCL cell lines (n = 6) and normal T cells (n = 3). Activation of mTOR signaling in TCL cell lines (n = 6) and normal T cells (n = 3). Western blotting was performed on 6 TCL cell lines of ALCL (Karpas 299, SUDHL1, and SR786) and CTCL (HuT 78, SeAx, and MyLa) subtypes, along with CD3+ T cells using phosphorylation site-specific antibodies for mTOR, AKT, and 4EBP1. Thomas E. Witzig et al. Blood 2015;126:328-335 ©2015 by American Society of Hematology

Effect of everolimus on TCL proliferation and survival. Effect of everolimus on TCL proliferation and survival. (A-D) After ALCL (n = 3) and CTCL (n = 3) cell lines were treated with everolimus as indicated, thymidine incorporation assay (A-B) and flow cytometry (C-D) assay was performed to a assess cell proliferation and survival inhibition. Thomas E. Witzig et al. Blood 2015;126:328-335 ©2015 by American Society of Hematology

Bar diagram of the outcome of each of the 16 patients with relapsed TCL treated with everolimus on this protocol. Bar diagram of the outcome of each of the 16 patients with relapsed TCL treated with everolimus on this protocol. Thomas E. Witzig et al. Blood 2015;126:328-335 ©2015 by American Society of Hematology

Effects of everolimus on mTOR signaling in TCL cell lines. Effects of everolimus on mTOR signaling in TCL cell lines. (A-B) ALCL and CTCL cell lines were treated with 1 and 10 nM of everolimus overnight. Whole cell lysate were then subjected to western blotting with phospho-specific antibodies to mTOR, S6, 4EBP1, and AKT as indicated. (C) Karpas 299, SR786, HuT 78, and MyLa TCL cell lines were treated with everolimus overnight and western blotting was performed using phosho-eIF4E antibody. Thomas E. Witzig et al. Blood 2015;126:328-335 ©2015 by American Society of Hematology

Effects of everolimus on cell cycle regulatory proteins in TCL Effects of everolimus on cell cycle regulatory proteins in TCL. (A-B) ALCL (A) and CTCL (B) TCL cell lines were treated with everolimus for 24 hours and then subjected to western blot analysis for cell cycle regulatory proteins, such as c-Myc, cyclin D1, an... Effects of everolimus on cell cycle regulatory proteins in TCL. (A-B) ALCL (A) and CTCL (B) TCL cell lines were treated with everolimus for 24 hours and then subjected to western blot analysis for cell cycle regulatory proteins, such as c-Myc, cyclin D1, and P27. Thomas E. Witzig et al. Blood 2015;126:328-335 ©2015 by American Society of Hematology

Change in plasma cytokine levels in 8 patients after 2 cycles of everolimus therapy. Change in plasma cytokine levels in 8 patients after 2 cycles of everolimus therapy. The best response to everolimus for these 8 patients was CR in patient 4; PR in patients 1, 2, 6, and 7; and SD in patients 3, 5, and 8. Thomas E. Witzig et al. Blood 2015;126:328-335 ©2015 by American Society of Hematology