Apoptosis Resistance in Cutaneous T Cell Lymphoma: Combination Therapies and Novel Therapeutic Targets
Final Report Abstract
Cutaneous T-cell lymphomas (CTCL) comprises a heterogeneous group of malignant lymphoid diseases characterized by the development of clonal, malignant T-cells that primarily reside in the skin. Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of CTCL and are characterized by high rates of progression and relapse, even after initially highly effective therapies. Accordingly, no curative treatment is yet available and a combination treatment of different therapies that inhibit different signaling pathways is being sought to achieve synergistic effects and reduce resistance. Our research on this is at various stages, with some results already prominently published, while other parts of the project are still in progress. Here, the effect of Bcl-2 inhibitors alone and in combination with the NF-κB inhibitor dimethyl fumarate (DMF) as well as the combination of DMF and extracorporeal photopheresis (ECP) on CTCL cells was investigated. These therapies presented as highly effective in CTCL cell death induction, and we also investigated the cellular mechanisms. In a translational approach, we also treated patients with some of the new therapies successfully and studied the mechanisms also in patient samples. To open up additional possibilities for combination therapies, in the end another research project is looking at the effect of HSP90 inhibitors, alone and in combination with DMF, in CTCL. These inhibitors have already shown promising results in very small amounts in terms of an efficient induction of cell death in cell lines and are therefore being investigated with patient samples. To sum up, our results suggest that the investigated therapeutic approaches may represent promising options for an effective ad well-tolerable treatment of CTCL.
Publications
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Combined inhibition of Bcl-2 and NFκB synergistically induces cell death in cutaneous T-cell lymphoma. Blood, 134(5), 445-455.
Froehlich, Tabea C.; Müller-Decker, Karin; Braun, Jana D.; Albrecht, Thomas; Schroeder, Anne; Gülow, Karsten; Goerdt, Sergij; Krammer, Peter H. & Nicolay, Jan P.
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Dimethyl fumarate treatment in relapsed and refractory cutaneous T-cell lymphoma: a multicenter phase 2 study. Blood, 142(9), 794-805.
Nicolay, Jan P.; Melchers, Susanne; Albrecht, Jana D.; Assaf, Chalid; Dippel, Edgar; Stadler, Rudolf; Wehkamp, Ulrike; Wobser, Marion; Zhao, Jing; Burghaus, Ina; Schneider, Sven; Gülow, Karsten; Goerdt, Sergij; Schürch, Christian M.; Utikal, Jochen S. & Krammer, Peter H.
